Jeffrey S. Barrett

Population Pharmacokinetic Studies in Pediatrics: Issues in Design and Analysis

The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.

Population Pharmacokinetics of Fluconazole in Young Infants

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Physiologically Based Pharmacokinetic (PBPK) Modeling in Children

This review summarizes the present status of physiologically based pharmacokinetic (PBPK) modeling and simulation (M&S) and its application in support of pediatric drug research. We address the reasons that PBPK is suited to the current needs of pediatric drug development and pharmacotherapy in light of the evolution in pediatric PBPK methodologies and approaches, which were originally developed for the purpose of toxicologic evaluation. Also discussed is the current degree of confidence in using PBPK to support pediatric drug development and registration and the key factors essential for robust results and broader adoption of pediatric PBPK M&S.

Population pharmacokinetic meta-analysis with efavirenz.

A population-based pharmacokinetic (PK) model has been developed for efavirenz based on 16 phase I studies. The combined data set consisted of 334 healthy volunteers, 2,907 efavirenz dose administrations and 9,342 measured plasma concentrations across a range of doses from 100-600 mg. The pharmacokinetic structural model was a 2-compartment model with first-order absorption with differentiation between single- and multiple-dose exposure to account for known hepatic cytochrome P450 induction of efavirenz metabolism. Model-building was performed on the index data set (66% of the total database), as a data-splitting technique was used to validate the final model using NONMEM. The final model confirmed the appropriateness of separate clearance terms for single and multiple dose administration (2.65 versus 10.2 l/h, respectively). Clearance increased with dose and frequency of administration. A lower clearance was predicted in Asians and Blacks relative to Caucasians. A slightly lower clearance was observed in females relative to males (9.08 compared to 10.2 l/h in males) and interactions on clearance due to co-administration of fluconazole, ritonavir, rifampin, indinavir and azithromycin were identified. The magnitudes of these effects were small and did not suggest dose adjustment in the various subpopulations. With little exception, these results agree with the findings from the non-compartmental analyses. The residual variability was 21% CV and the intersubject variation in CL/F and V/F was 48 and 85%, respectively. The phase I meta-analysis was able to substantiate the pharmacokinetic characteristics of efavirenz derived from the composite of individual well-defined studies. The model was deemed adequate for subsequent evaluation in HIV-infected patients. Covariates and outlier classes identified in this phase I meta-analysis were similarly identified in subsequent analyses of patient data.

Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants.

Background: Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist. Methods: Our population pharmacokinetic model derived from 357 fluconazole plasma concentrations from 55 infants (23–40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient populations pharmacokinetic response to fluconazole to predict fluconazole exposure (median: 10th and 90th percentile population variability range) after 3, 6, and 12 mg/kg dosing. Results: For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/d in the first 90 days after birth is needed to achieve an area under the concentration curve (AUC) of >400 mg*h/L and an AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 &mgr;g/mL in ≥90% of <30 week gestation infants and 80% of 30 to 40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early prevention of candidiasis in 23 to 29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations ≥2 or 4 &mgr;g/mL, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with serum creatinine ≥1.3 mg/dL have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours. Conclusions: A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis, twice weekly prophylaxis regimens can provide adequate exposure when unit specific MICs are taken into account.

Fluconazole Loading Dose Pharmacokinetics and Safety in Infants

Background: Invasive candidiasis is a leading cause of morbidity and mortality in critically ill infants. Prompt administration of fluconazole and achievement of the therapeutic target (area under the curve 0 to 24 hours >400 mg*h/L) improve outcomes in candidemic patients. A loading dose of fluconazole is advised for older patients but has not been evaluated in infants. We sought to determine the pharmacokinetics and safety of a fluconazole loading dose in infants at risk for invasive fungal infection. Methods: We enrolled 10 hospitalized infants <60 days old with suspected systemic fungal infection in this open-label study; 9 received a 25-mg/kg fluconazole loading dose followed by a maintenance dose of 12 mg/kg every 24 hours for 4 additional days. Plasma samples were obtained following the loading and steady-state doses (doses 3–5). We used a 1-compartment model to fit the data to estimate pharmacokinetic indices. Results: Data from 57 drug concentrations obtained from 8 infants (median postnatal age, 16 days [interquartile range, 13–32] and median gestational age, 37 weeks [35–38]) showed that the median fluconazole area under the curve 0 to 24 hours (mg*h/L) in this population was 479 (347–496). Of the 8 infants who received the loading dose, 5 (63%) achieved the therapeutic target on the first day of dosing, and all infants achieved a fluconazole 24-hour trough concentration >8 &mgr;g/mL. No adverse events were thought to be related to fluconazole therapy. Conclusions: A loading dose of fluconazole (25 mg/kg) was safe in this small cohort of young infants and achieved the therapeutic target more rapidly than traditional dosing.

Pharmacometrics: A Multidisciplinary Field to Facilitate Critical Thinking in Drug Development and Translational Research Settings

Pharmacometrics has evolved beyond quantitative analysis methods used to facilitate decision making in drug development, although the application of the discipline in this arena continues to represent the primary emphasis of scientists calling themselves pharmacometricians. While related fields populate and interface with pharmacometrics, there is a natural synergy with clinical pharmacology due to common areas of research and the decision‐making expectation with respect to evolving conventional and translational research paradigms. Innovative and adaptable training programs and resources are essential in this regard as both disciplines promise to be key elements of the clinical research workplace of the future. The demand for scientists with pharmacometrics skills has risen substantially. Likewise, the salary garnered by those with these skills appears to be surpassing their counterparts without such backgrounds. Given the paucity of existing training programs, available training materials, and academic champions, a virtual faculty and online curriculum would allow students to matriculate into one of several programs associated with their advisor but take instruction from faculty at multiple institutions, including instructors in both industrial and regulatory settings. Flexibility in both the curriculum and the governance of the degree would provide the greatest hope of addressing the short supply of trained pharmacometricians.

The In Silico Child: Using Simulation to Guide Pediatric Drug Development and Manage Pediatric Pharmacotherapy

Significant gains have been made in the appreciation of pediatrics as an important population in which rationale pharmacotherapy guidance is warranted but often currently lacking. Although the regulatory framework for major improvements in pediatric drug development was implemented in Europe a decade later than the United States, recent efforts, including the 2007 “Better Medicines for Children” initiative, indicate that the awareness of this problem is indeed a global phenomenon. Nevertheless, there still remains a gap between the awareness and the implementation of rationale and scientifically based drug development and applied pharmacotherapy in children. Specifically, a vision of how best to move from empiricism toward a plan that incorporates biologic knowledge about the maturation of physiologic processes as well as the drug‐ and disease‐specific knowledge generated from drug development and applied pharmacotherapy in adults must evolve from the present intentions. Modeling and simulation approaches can facilitate such a vision that ultimately should provide benefit to pediatric patients. Although recent examples of pediatric in silico approaches are compelling, their ultimate value may be in the identification of data and studies that better guide drug therapy and in the education of pediatric caregivers to the principles of clinical pharmacology that underlie optimal pharmacotherapeutic decisions in children.

Busulfan in Infant to Adult Hematopoietic Cell Transplant Recipients: A Population Pharmacokinetic Model for Initial and Bayesian Dose Personalization

Purpose: Personalizing intravenous busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1–66 years) that accounts for differences in age and body size. Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models. Results: A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size—specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults. Clin Cancer Res; 20(3); 754–63. ©2013 AACR.

Rhabdomyolysis reports show interaction between simvastatin and CYP3A4 inhibitors

To assess spontaneous reports of rhabdomyolysis associated with simvastatin (SV) and pravastatin (PV) for evidence of CYP3A4 interaction. Clinical trial results advocate cholesterol lowering in high‐risk patients including diabetics and the elderly. Given the association between advancing age, metabolic, and cardiovascular disease, many patients are treated with concomitant medications upon statin initiation. Although statins are generally safe, minor and severe adverse reactions arise, especially when given to patients taking concomitant medications that inhibit the statin clearance and lead to increased statin plasma concentration.