Physiologically-based pharmacokinetic models for children: Starting to reach maturation?

Developmental changes in children can affect the disposition and clinical effects of a drug, indicating that scaling an adult dose simply down per linear weight can potentially lead to overdosing, especially in very young children. Physiologically-based pharmacokinetic (PBPK) models are compartmental, mathematical models that can be used to predict plasma drug concentrations in pediatric populations and acquire insight into the influence of age-dependent physiological differences on drug disposition. Pediatric PBPK models have generated attention in the last decade, because physiological parameters for model building are increasingly available and regulatory guidelines demand pediatric studies during drug development. Due to efforts from academia, PBPK model developers, pharmaceutical companies and regulatory authorities, examp

Chloroquine dosing recommendations for pediatric COVID-19 supported by modeling and simulation

As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control COVID-19 experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing WHO dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in AUC0-70h the optimal CHQ dose was determined in children of different ages compared to adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years and 44 mg/kg for adolescents and adults, not to exceed 3300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-

Developmental patterns in human blood–brain barrier and blood–cerebrospinal fluid barrier ABC drug transporter expression

When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9–39 weeks), 17 neonates (GA range 24.6–41.3 weeks, PNA range 0.004–3.5 weeks), 8 children (PNA range 0.1–3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not det

Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule

: Background: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. Methods: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. Results: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520–770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. Conclusion: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug–drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates