A Pharmacokinetic Standard for Babies and Adults

Merchant N.M., Azzopardi D.V., Hawwa A.F., McElnay J.C., Middleton B., Arendt J., Arichi T., Gressens P., Edwards A.D.

Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials.Melatonin was administered to 18 preterm infants in doses ranging from 0.04-0.6 μg kg(-1) over 0.5-6 h. Pharmacokinetic profiles were analyzed individually and by population methods.Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 μg kg(-1) h(-1) for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml(-1) . On population pharmacokinetics, clearance was 0.045 l h(-1) , volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates.A 2 h infusion of 0.1 μg kg(-1) h(-1) increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants.

Hawwa A.F., Westwood P.M., Collier P.S., Millership J.S., Yakkundi S., Thurley G., Shields M.D., Nunn A.J., Halliday H.L., McElnay J.C.

To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition.Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling.A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46.Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Polasek T.M., Patel F., Jensen B.P., Sorich M.J., Wiese M.D., Doogue M.P.

To determine the effect of increasing adult age on predicted metabolic drug clearance.Predicted metabolic drug clearances (CLPT ) were determined using in vitro-in vivo extrapolation coupled with physiological-based pharmacokinetic modelling and simulation (IVIVE-PBPK) in Simcyp®. Simulations were conducted using CYP-selective 'probe' drugs with subjects in 5 year age groups (20-25 to 90-95 years). CLPT values were compared with human pharmacokinetic data stratified according to age (young = 20-40 years and elderly = 65-85 years) and gender. Age-related changes in the physiological parameters used for IVIVE of CLPT were described.Predicted metabolic drug clearances decreased with increasing adult age to approximately 65-70 years: caffeine from 1.5 to 1.0 ml min(-1) kg(-1) (a 33% decrease), S-warfarin from 0.100 to 0.064 ml min(-1) kg(-1) (36%), S-mephenytoin from 4.1 to 2.5 ml min(-1) kg(-1) (39%), desipramine from 10.6 to 7.3 ml min(-1) kg(-1) (31%) and midazolam from 5.4 to 3.9 ml min(-1) kg(-1) (27%). Except for S-mephenytoin, predictions were within 3.5-fold of clearances from clinical studies when stratified by age and gender. A trend towards higher CLPT was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine CLPT decreased with increasing adult age: mean microsomal protein g(-1) of liver, liver weight, hepatic blood flow and human serum albumin concentration.Decreased metabolic clearance in the elderly was predicted by Simcyp® and was generally consistent with limited clinical data for four out of five drugs studied and the broader literature for drugs metabolized by CYP enzymes. IVIVE-PBPK may be increasingly useful in predicting metabolic drug clearance in the elderly.

Hendriksen I.C., Maiga D., Lemnge M.M., Mtove G., Gesase S., Reyburn H., Lindegardh N., Day N.P., von Seidlein L., Dondorp A.M., Tarning J., White N.J.

ABSTRACT Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.)

Shellhaas R.A., Ng C.M., Dillon C.H., Barks J.D., Bhatt-Mehta V.

Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes.Level 3 neonatal ICU.Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia.None.A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not).Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital.Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

Mohammed B.S., Engelhardt T., Cameron G.A., Cameron L., Hawksworth G.M., Hawwa A.F., McElnay J., Helms P.J., McLay J.S.

To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age.After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM.One hundred and fifty-nine blood samples from 33 children aged 1.8-15 yr, weight 13.7-56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V(1) (central volume of distribution), Q (inter-compartmental clearance), and V(2) (peripheral volume of distribution) were: 16.51×(WT/70)(0.75), 28.4×(WT/70), 11.32×(WT/70)(0.75), and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V(1) and V(2) in litres).In children aged 1.8-15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V(1), V(2)).

McLeay S.C., Morrish G.A., Kirkpatrick C.M., Green B.

Background: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. Aim: The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. Methods: Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a ‘nonlinear’ relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting ‘other’ relationships (e.g. linear increase in CL with TBW, ideal body weight or height). Results: A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)2/3, or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. Conclusions: To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.

Drover D.R., Hammer G.B., Anderson B.J.

Ketorolac tromethamine (ketorolac) administration reduces postoperative opioid requirements. The pharmacokinetic characteristics of intranasal ketorolac tromethamine in children have not been characterized. Our objective of this study was to determine the pharmacokinetics of a single intranasal dose of ketorolac in adolescent patients.Twenty surgical patients, ages 12 to 17 years, were enrolled. After surgery, subjects received intranasal ketorolac 15 mg (weight ≤50 kg) or 30 mg (weight >50 kg) using a proprietary administration system. Blood samples were obtained for ketorolac assay at baseline (within 15 minutes before the dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose. A population analysis was undertaken using nonlinear mixed-effects models. Parameter estimates were standardized to a 70-kg person.The intranasal dosing in adolescents was well tolerated with minimal adverse effects. A 1-compartment model with first-order absorption and elimination was satisfactory to describe time-concentration profiles. Population parameter estimates (between subject variability) were clearance (CL/F) 2.05 L/h (60.5%), volume of distribution (V/F) 15.2 L (32.4%), absorption half-life (t(1/2)abs) 0.173 hour (25.0%). Time to peak concentration (Tmax) was 52 minutes (SD 6 minutes).Administration of ketorolac by the intranasal route resulted in a rapid increase in plasma concentration and may be a useful therapeutic alternative to IV injection in adolescents because plasma concentrations attained with the device are likely to be analgesic (investigational new drug no. 62,829).

Hullett B., Salman S., O'Halloran S., Peirce D., Davies K., Ilett K.

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

Wang C., Peeters M.Y., Allegaert K., Blussé van Oud-Alblas H.J., Krekels E.H., Tibboel D., Danhof M., Knibbe C.A.

To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best. A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight.

Holford N.H., Ma S.C., Anderson B.J.

Morphine is widely used throughout the human life span. Several pharmacokinetic models have been proposed to predict how morphine clearance changes with weight and age. This study uses a large external data set to evaluate the ability of pharmacokinetic models to predict morphine doses.A data set of morphine clearance estimates was created from published reports in premature neonates, full-term neonates, infants, children, and adults. This external data set was used to evaluate published models for morphine clearance as well as other models proposed for use in neonates and infants. Morphine clearance predictions were used to predict morphine dose rates to achieve similar target concentrations in all age groups.An allometric ¾ power model using weight combined with a sigmoid maturation model using postmenstrual age successfully predicted the morphine dose rate (within 25% of target) in all age groups except infants [predicted dose 30% under target (95% CI, 7-46%)]. Other published models based on empirical allometric scaling all made unacceptable predictions (>100% of target) in at least one age group.Clearance based on empirical allometric scaling predicted unacceptable doses. Theory-based allometric scaling combined with a maturation function has been confirmed by external evaluation to provide a sound basis for describing clearance and predicting morphine doses in humans of all ages.

Bouazza N., Urien S., Hirt D., Frange P., Rey E., Benaboud S., Foissac F., Blanche S., Tréluyer J.

To evaluate the pharmacokinetics of tenofovir in children and the influence of covariates [body weight (BW), age, cotreatments]. The main goal was then to suggest for the first time the dose of tenofovir disoproxil fumarate (TDF) to give in children.Tenofovir concentrations were monitored on a routine basis and measured in 93 children aged 5 to 18 years; 283 tenofovir plasma concentrations were used to perform a population pharmacokinetic analysis.A 2-compartment model adequately described the data. A BW allometric scaling was used; and the typical population estimates (interindividual variability), standardized for 70 kg, for apparent clearance, central and peripheral volume of distribution, intercompartmental clearance, and absorption rate constant, were 59.8 L·h⁻¹ (0.48), 386 L (1.39), 666 L, 92.8 L·h⁻¹ and 0.43 h⁻¹, respectively. TDF clearance increased significantly with BW and decreased with lopinavir/ritonavir (LPV/r) coadministration, thus these factors were used to propose doses for children. Dosing scheme, according BW and LPV/r coadministration were simulated to produce the same 24-hr exposure as adults after 300-mg TDF dose.Children without LPV/r should receive: 150 mg TDF from 20 to 30 kg, 225 mg TDF from 30 to 40 kg, and the adult dosage of 300 mg TDF over 40 kg. To avoid risk of renal toxicity, TDF dose should be decreased when coadministrated with LPV/r, children should receive 150 mg TDF from 20 to 40 kg, 225 mg TDF from 40 to 55 kg, and the adult dosage of 300 mg TDF over 55 kg.

Aarons L., Sadler B., Pitsiu M., Sjövall J., Henriksson J., Molnár V.

The aim was to characterize ropivacaine and 2',6'-pipecoloxylidide (PPX) pharmacokinetics and factors affecting them in paediatric anaesthesia.Population pharmacokinetics of ropivacaine and its active metabolite PPX were estimated after single and continuous ropivacaine blocks in 192 patients aged 0-12 yr from six pooled published studies. Unbound and total ropivacaine and PPX plasma concentration and PPX urinary excretion data were used for non-linear mixed-effects modelling by NONMEM. Covariates included age, body weight, gender, ethnic origin, ASA, site and method of administration, and total dose.One-compartment first-order pharmacokinetic models incorporating linear binding of ropivacaine and PPX to α(1)-acid glycoprotein were used. After accounting for the effect of body weight, clearance of unbound ropivacaine and PPX reached 41% and 89% of their mature values, respectively, at the age of 6 months. Ropivacaine half-life decreased with age from 13 h in the newborn to 3 h beyond 1 yr. PPX half-life differed from 19 h in the newborn to 8-11 h between 1 and 12 months to 17 h after 1 yr. Simulations indicate that for a single caudal block, the recommended dose could be increased by a factor of 2.9 (0-1 month group) and 6.3 (1-12 yr group) before the unbound plasma concentrations would cross the threshold for systemic toxicity. Corresponding factors for continuous epidural infusion are 1.8 and 4.9.Ropivacaine and PPX unbound clearance depends on body weight and age. The results support approved dose recommendations of ropivacaine for the paediatric population.

Thuo N., Ungphakorn W., Karisa J., Muchohi S., Muturi A., Kokwaro G., Thomson A.H., Maitland K.

Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown.Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC(0-24)/MIC ratio of ≥125.Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8-102 months. Absorption was generally rapid but variable; C(max) ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h) = 42.7 (L/h/70 kg) × [weight (kg)/70](0.75) × [1 + 0.0368 (Na(+) - 136)] × [1 - 0.283 (high risk)] and V (L) = 372 × (L/70 kg) × [1 + 0.0291 (Na(+) - 136)]. Estimates of AUC(0-24) ranged from 8 to 61 mg·h/L. The breakpoint for Gram-negative organisms was

Bouazza N., Hirt D., Blanche S., Frange P., Rey E., Tréluyer J., Urien S.

ABSTRACT Lamivudine concentration-time courses were described for a very large range of ages to study the effects of body weight and maturation on lamivudine pharmacokinetics and to check the consistency of dosing recommendations. Lamivudine concentrations were monitored on a routine basis to produce concentrations similar to the known values in adults. Concentrations were measured in 580 children from 2 days to 18 years old. A total of 2,106 plasma lamivudine concentrations were measured, and a population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.1 software. A two-compartment model adequately described the data. After standardization for a mean standard body weight by using an allometric model, age also had a significant effect on clearance maturation. Typical population estimates (percent interindividual variability) standardized for 70 kg of the apparent clearance, including central and peripheral volumes of distribution, intercompartmental clearance, and absorption rate constant, were 31 liters·h −1 (32%), 76.4 liters (77%), 129 liters, 5.83 liters·h −1 , and 0.432 h −1 , respectively. According to the model, elimination clearance (liters/h/70 kg) increases gradually during the first years of life. Theoretical doses needed to reach the range of 24 h of exposure observed in adults were calculated: to be closer to adult exposure, children should receive 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.

Yaliniz A., El Hassani M., Blanchard A.C., Marsot A.

Mukap M., Sprod C., Yoo O., Tefuarani N., Vince J., Laman M., Page-Sharp M., Moore B.R., Batty K.T., Davis T.M., Salman S., Manning L.

ABSTRACT Amoxicillin plus gentamicin is the recommended first-line empiric therapy for neonates with infection. Guidelines vary widely in dose (mg/kg), dose frequency, and adjustments according to post-menstrual age (PMA) and post-natal age (PNA). We aimed to develop a population pharmacokinetic (PK) model for amoxicillin in neonates with clinical evidence of sepsis and design optimal dosing regimens. One hundred seventy-seven neonates receiving intravenous amoxicillin for infection were enrolled in a prospective, observational PK study in Papua New Guinea (PNG). The probability of PK-pharmacodynamic target attainment (PK-PD PTA) was determined based on minimum inhibitory concentrations (MIC) and the proportion of time concentrations that remained above these values (%T > MIC). Neonates with concentrations > 140 mg/L were considered to be at increased risk of amoxicillin neurotoxicity. A population PK model was developed. Simulations tested existing guidelines and proposed simplified regimens. The median PMA and PNA were 38 (37–40) weeks and 0 (0–2) days, respectively. From simulations, existing regimens with 50 or 100 mg/kg doses were associated with higher potential neurotoxic concentrations (24.9% and 84.5%, respectively). With the existing 30 mg/kg PNG regimen, neonates receiving twice-daily dosing between 3 and 7 days were systematically underdosed. A proposed 30 mg/kg regimen, with twice-daily dosing for the first 2 days PNA and three times daily from day 3, provides an optimal balance between the probability of PK-PD target attainment while minimizing toxicity. For fixed volume dosing, using 52 mg (0.25 mL of 250 mg in 1.2 mL) for those <3 kg and 104 mg (0.5 mL) for those ≥3 kg is proposed.

Waalewijn H., Almett M., Wasmann R.E., Cressey T.R., Easterbrook P., Olumese P.E., Hesseling A.C., Garcia-Prats A.J., Tarning J., Turkova A., Viney K., Svensson E.M., Colbers A., Were W.M., Denti P., et. al.

Bokor A.J., Holford N., Hannam J.A.

Abstract The time course of biomarkers (e.g., acute phase proteins) are typically described using days relative to events of interest, such as surgery or birth, without specifying the sample time. This limits their use as they may change rapidly during a single day. We investigated strategies to impute missing clock times, using procalcitonin for population modelling as the motivating example. 1275 procalcitonin concentrations from 282 neonates were available with dates but not sample times (Scenario 0). Missing clock times were imputed using a random uniform distribution under three scenarios: (1) minimum sampling intervals (8–12 h); (2) procalcitonin concentrations increase for postnatal days 0–1 then decrease; (3) standard sampling practice at the study hospital. Unique datasets (n = 100) were created with scenario-specific imputed clock times. Procalcitonin was modelled for each scenario using the same non-linear mixed effects model using NONMEM. Scenarios were evaluated by the NONMEM objective function value compared to Scenario 0 (∆OFV) and with visual predictive checks. Scenario 3, based on standard sampling practice at the study hospital, was the best imputation procedure with an improved objective function value compared to Scenario 0 (∆OFV: -62.6). Scenario 3 showed a shorter lag time between the birth event and the procalcitonin concentration increase (average: 12.0 h, 95% interval: 9.7 to 14.3 h) compared to other scenarios (averages: 15.3 to 18.7 h). A methodology for selecting imputation strategies for clock times was developed. This may be applied to other problems where clock times are missing.

Ndzamba B., Denti P., McIlleron H., Smith P., Mthiyane T., Rustomjee R., Onyebujoh P., Reséndiz-Galván J.E.

ABSTRACT Ethambutol is used to treat tuberculosis (TB) in individuals living with HIV. Low concentrations of ethambutol have been reported in patients dosed with the World Health Organization (WHO)-recommended first-line regimen. We analyzed the pharmacokinetics of ethambutol in 61 HIV-positive individuals diagnosed with drug-sensitive TB enrolled in the tuberculosis and highly active antiretroviral therapy (TB-HAART) study. Participants started on TB treatment and were randomized to early or later introduction of efavirenz-based antiretroviral treatment. We explored potential covariate effects and evaluated the current WHO dosing recommendations for ethambutol in drug-susceptible and multidrug-resistant (MDR)-TB. A two-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption best described the pharmacokinetics of ethambutol. Clearance was estimated to be 40.3 L/h for a typical individual with a fat-free mass (FFM) of 42 kg. The Antib-4 formulation had 26% higher bioavailability and slower mean transit time by 37% compared with Rifafour. Simulations showed that individuals in the lower weight bands (<55 kg) who were administered ethambutol at WHO-recommended doses had relatively low drug exposures. These individuals would need doses of 825 mg if their body weight is <37.9 kg and 1,100 mg if it is between 38 and 54.9 kg to achieve the reference maximum concentrations of 2–6 mg/L and an area under the concentration-time curve (0–24) of 16–29 mg·h/L. To achieve these targets in MDR-TB treatment, a dose increment of 400 mg (extra tablet) would be required for individuals in the lower weight band (<46 kg). Our dose adjustments are consistent with the literature and can be recommended for consideration by the WHO for first-line drug-susceptible and MDR-TB treatment.

Ravix A., Gotta V., Pfister M., Berger C., Glauser A., Paioni P., Csajka C., Guidi M.

AbstractAmoxicillin is commonly used to treat erythema migrans in the first stage of Lyme disease in children, with a recommended dose of 50 mg/kg/day, administered three times a day (q8h). This model‐based simulation study aimed to determine whether splitting the same daily dose into two administrations (q12h) would provide comparable drug exposure. A pharmacokinetic model suitable for a pediatric population (age: 1 month to 18 years, weight: 4–80 kg) was selected through a literature review. Simulations were performed with 15,000 virtual patients receiving 16.67 mg/kg/dose q8h, 25 mg/kg/dose q12h, or other q12h dosing variations. The target therapeutic level was defined by the percentage of time that the unbound drug concentration remained above the minimum inhibitory concentration (% fT > MIC) specific to Borrelia burgdorferi, with MICs of 0.06, 0.25, 1, 2, and 4 mg/L, requiring at least 40% and 50% of time for effective treatment. Probability of target attainment (PTA) was considered acceptable if it exceeded 50%, allowing for comparison of dosing schedules. Results indicated that the 50 mg/kg/day divided q12h regimen provided similar drug exposure to the q8h regimen for MICs below 2 mg/L (PTAs >50%). For a MIC of 2 mg/L, PTA was achieved with a higher dose of 30 mg/kg/dose q12h. However, for a MIC of 4 mg/L, the PTA criterion was not met. These findings suggest that a twice‐daily dosing of 25 mg/kg/dose provides comparable bactericidal activity to the thrice‐daily regimen for MICs between 0.06 and 1 mg/L. This simplified regimen may improve adherence and treatment implementation in children.

Pepin X.J., Johansson Soares Medeiros J., Deris Prado L., Suarez Sharp S.

Background/Objectives: The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has undertaken the development of an age-appropriate dispersible tablet to be taken with water for all age groups from birth to adolescence. The primary objective of this work was to develop and validate a physiologically-based biopharmaceutics model (PBBM) in GastroPlusTM, to link the product’s in vitro performance to the observed pharmacokinetic (PK) data in adults and children. Methods: The PBBM was developed based on measured or predicted physico-chemical and biopharmaceutical properties of INH and RIF. The metabolic clearance was specified mechanistically in the gut and liver for both parent drugs and acetyl-isoniazid. The model incorporated formulation related measurements such as dosage form disintegration and dissolution as inputs and was validated using extensive literature as well as in house clinical data. Results: The model was used to predict the exposure in children across the targeted dosing regimen for each age group using the new age-appropriate formulation. Probabilistic models of efficacy and safety versus exposure, combined with real world data on children, were utilized to assess drug efficacy and safety in the target populations. Conclusions: The model predictions (systemic exposure) along with clinical data from the literature linking systemic exposure to clinical outcomes confirmed that the proposed dispersible pediatric tablet and dosing regimen are anticipated to be as safe and as effective as adult formulations at similar doses.

van Valkengoed D.W., Krekels E.H., Knibbe C.A.

Scaling approaches are used to describe or predict clearance for paediatric or obese populations from normal-weight adult values. Theoretical allometry assumes the existence of a universal bodyweight-based scaling relationship. Although theoretical allometry is highly disputed, it is commonly applied in pharmacological data analyses and clinical practice. The aim of the current review is to (1) increase pharmacologists’ understanding of theoretical allometry to better understand the (implicit) assumptions and (dis)advantages and (2) highlight important methodological considerations with the application of this methodology. Theoretical allometry originated in an empirical, and later debated, observation by Kleiber of a scaling exponent of 0.75 between basal metabolic rate and body mass of mammals. The mathematical framework of West, Brown, and Enquist provides one possible explanation for this value. To date, multiple key assumptions of this framework have been disputed or disproven, and an increasing body of evidence is emerging against the existence of one universal allometric exponent. The promise of ease and universality of use that comes with theoretical approaches may be the reason they are so strongly sought after and defended. However, ecologists have suggested that the theory should move from a ‘Newtonian approach’, in which physical explanations are sought for a universal law and variability is of minor importance, to a ‘Darwinian approach’, in which variability is considered of primary importance for which evolutionary explanations can be found. No scientific support was found for the application of allometry for within-species scaling, so the application of basal metabolic rate-based scaling principles to clearance scaling remains unsubstantiated. Recent insights from physiologically based modelling approaches emphasise the interplay between drugs with different properties and physiological variables that underlie drug clearance, which drives the variability in the allometric scaling exponent in the field of pharmacology. To deal with this variability, drug-specific or patient-specific adaptations to theoretical allometric scaling are proposed, that introduce empiric elements and reduce the universality of the theory. The use of allometric scaling with an exponent of 0.75 may hold empirical merit for paediatric populations, except for the youngest individuals (aged ≤ 5 years). Nevertheless, biological interpretations and extrapolation potential attributed to models based on 0.75 allometric scaling are theoretically unfounded, and merits of the empirical application of this function should, as for all models, always be supported by appropriate model validation procedures. In this respect, it is not the value of the allometric exponent but the description and prediction of individual clearance values and drug concentrations that are of primary interest.

Suzuki Y., Matsunaga N., Aoyama T., Ogami C., Hasegawa C., Iida S., To H., Kitahara T., Tsuji Y.

AbstractThe pharmacokinetics (PKs) of mycophenolic acid (MPA) exhibit considerable complexity and large variability. We developed a population pharmacokinetic (popPK) model to predict the complex PK of MPA by examining an absorption model. Forty‐two patients who had undergone renal transplantation were included in this study. popPK analysis, incorporating several absorption models, was performed using the nonlinear mixed‐effects modeling program NONMEM. The MPA area under the concentration‐time curve at 0–12 h (AUC0–12) was simulated using the final model to calculate the recommended dose. The PK of MPA was adequately described using a two‐compartment model incorporating sequential zero‐ and first‐order absorption with lag time. Total body weight, renal function (RF), and posttransplantation day (PTD) were included as covariates affecting MPA PK. The final model estimates were 7.56, 11.6 L/h, 104.0 L, 17.3 L/h, 169.0 L, 0.0453, 0.283, and 1.95 h for apparent nonrenal clearance, apparent renal clearance, apparent central volume of distribution, apparent intercompartmental clearance, apparent peripheral volume of distribution, absorption half‐life, lag time, and duration of zero‐order absorption, respectively. Simulation results showed that a dose regimen of 500–1000 mg twice daily is recommended during the early posttransplantation period. However, dose reduction could be required with increased PTD and decreased RF. The complex PK of MPA was explained using an absorption model. The developed popPK model can provide useful information regarding individual dosing regimens based on PTD and RF.

Jirasomprasert T., Tian L., You D., Wang Y., Dong L., Zhang Y., Hao G., van den Anker J., Wu Y., Tang B., Zhao W., Zheng Y.

We aimed to determine the piperacillin disposition and optimize the dosing regimens for infants and children with pneumonia. An opportunistic sampling strategy was used in this pharmacokinetic study. High-performance liquid chromatography was used to measure the concentrations of piperacillin in plasma samples. A population pharmacokinetic model was conducted using NONMEM. The pharmacokinetic data of 90 samples from 64 infants and children with pneumonia (age range: 0.09–1.72 years for infants and 2.12–11.10 years for children) were available. A two-compartment model with first-order elimination was the most suitable model to describe the population pharmacokinetics of piperacillin. A covariate analysis indicated that body weight and age were significant factors affecting clearance. Monte Carlo simulations showed that a 50-mg/kg every 8 h or every 12 h dosing regimen results in underdosing. Results both in infants and children showed that an extended infusion (3 h) of various dosing regimens (80, 100, or 130 mg/kg) three times daily or a 300-mg/kg continuous infusion can reach a therapeutic level based on the chosen target for the probability of target attainment threshold of 70%, 80%, and 90% at minimum inhibitory concentration breakpoints of 8 mg/L and 16 mg/L. A population pharmacokinetic model was obtained to evaluate the disposition of piperacillin, and the optimal dosing regimens were provided for use in infants and children with pneumonia.

Tang F., Ng C.M., Horn J., Bada H.S., Leggas M.

The No‐POPPY study (NCT03396588), a double‐blind, randomized trial compared morphine with clonidine therapy for neonatal opioid withdrawal syndrome (NOWS) and found that the duration of treatment was similar across groups. This is significant because perinatal use of morphine has the potential for neurodevelopmental consequences. Still, the clonidine group reached symptom stabilization (Finnegan score (FS) < 8) later than the morphine group and had a more significant number of patients who required adjunct therapy. However, the mean FS was consistently lower in the clonidine group after day 6. This prompted us to use pharmacokinetic (PK) and parametric time‐to‐event (TTE) modeling to simulate dosage schedules that may decrease the time to stabilization and reduce the need for adjunct therapy. Population PK (popPK) analysis was conducted, and the final model was a one‐compartment model with first‐order absorption and elimination, incorporating allometric scaling and age effect on apparent clearance (CL/F) and apparent volume (V/F). The population estimates for CL/F and V/F were 13.6 L/h/70 kg and 416 L/70 kg, respectively, similar to the reported values. A Weibull model described the TTE data best, followed by incorporating predicted average concentrations to yield the final Weibull accelerated failure time model. Simulations of dosing strategies showed that increasing both the starting and maximum doses could potentially shorten the time to stabilization, and thus, length of treatment and hospital stay. Given the hypothesis‐generating nature of this analysis, the recommended dosing regimens should be tested prospectively to evaluate their benefits.

Mohmaed Ali M.I., Nijstad A.L., Boosman R.J., Crombag M.B., Barnett S., Veal G.J., Lalmohamed A., van Erp N.P., Steeghs N., Zwaan C.M., Beijnen J.H., Siebinga H., Huitema A.D.

The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin. A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages. First, the effect of age in young patients was investigated, by adding a maturation function on clearance (CL), the central compartment (V1) and peripheral compartments (V2 and V3). Second, the impact of ageing was investigated by adding a maximal effect (Emax) function on CL, V1, V2, and V3. To investigate the overall impact of age on doxorubicin exposure, various simulations were conducted. A total of 168 patients (age: 0.11–90 years) with 555 doxorubicin samples were included. The maturation function was relevant for V1 and V2 (13.1 and 23.7 L, respectively), leading to an increase in V1 and V2 with increasing age. In contrast, adding an Emax function only impacted V3 (1063L), resulting in a decrease of V3 with age. Simulations showed no clinically relevant difference in the exposure of doxorubicin between age groups. A population pharmacokinetic model with data across the age range showed that age predominantly affected volumes of distribution of the central and peripheral compartments. These effects were not considered to be clinically relevant based on performed simulations. This supports the use of currently used doxorubicin dosages of 1 mg/kg for infants and toddlers < 10 kg and body surface area-based dosing for other patients.

Duarte Lima J.M., Sousa B.B.

In a world where children's health and well-being are non-negotiable priorities, this research emerges completely at the intersection between socially responsible marketing and the promotion of children's health, meticulously focusing its attention on the pharmaceutical sector, notably the involving the field of dermocosmetics. The analysis addresses in detail the fundamentals of socially responsible marketing, examining how ethical communication strategies and sustainable practices influence consumer perception and behavior. Consumer behavior is explored identically, investigating the role of brand attachment and examining how the emotional connection between consumers and brands can be strengthened or compromised, through the marketing strategies adopted. It is imperative to highlight quality management as the foundation on which consumer trust is built. This study includes a detailed review of academic and professional literature relevant to understanding the key concepts and practices of socially responsible marketing in the context of children's health.

Qian Y.

Fan L., Guo H., Zhao Y., Li Y., Wang W., Huang J., Hu Y., Zou J., Chen F.

BackgroundThe main challenges faced when using sirolimus in children with vascular anomalies (VAs) still include significant pharmacokinetic (PK) variability, uncertainty in the target concentration range, as well as inconsistencies in initial dosing and dosing frequency. The aim of this study is to establish a new population pharmacokinetic (PPK) model for children with VAs to guide the individualized use of sirolimus.MethodsA PPK study was performed using data from children with VAs who received sirolimus between July 2017 and April 2022. A nonlinear mixed-effect modeling with a one-compartment model structure was applied. Monte Carlo simulation was employed to propose specific dosing recommendations to achieve the target trough concentrations (Ctrough) of 5–15 ng/mL.ResultsIn total, 134 blood concentrations from 49 pediatric patients were used to characterize the sirolimus pharmacokinetics. Covariate analysis identified body weight (BW) as a significant factor affecting clearance (CL) in the final PPK model. The typical clearance rate and distribution volume, standardized to a BW of 16 kg, were 4.06 L/h (4% relative standard error, RSE) and 155 L (26% RSE), respectively. Optimal dosing regimens were simulated for different BWs. For a twice-daily regimen, the recommended doses were 0.05, 0.06, 0.07, and 0.08 mg/kg/day for BW of &lt;10, 10–20, 20–40, and ≥40 kg, respectively; for a once-daily regimen, the recommended doses were 0.06, 0.07, 0.08, and 0.09 mg/kg/day for BW of &lt;10, 10–30, 30–50, and ≥50 kg, respectively. Notably, sirolimus Ctrough could be maintained between 5–15 ng/mL across various dosing frequencies based on the recommended dosing regimen.ConclusionWe established a PPK model of sirolimus for children with VAs and proposed an initial dosing strategy. Integrating initial dose and medication frequency recommendations into sirolimus’ guidelines will broaden its clinical options and simplify the clinical management for childhood VAs.