[Abstract unavailable

Physiologically‐based pharmacokinetic ( PBPK ) modeling allows assessment of the covariates contributing to the large pharmacokinetic ( PK ) variability of tacrolimus; these include multiple physiological and biochemical differences among patients. A PBPK model of tacrolimus was developed, including a virtual population with physiological parameter distributions reflecting renal transplant patients. The ratios of predicted to observed dose‐normalized maximum plasma concentration (C max ), 0–12‐hour area under the concentration–time curve ( AUC 0–12 hour ), and trough plasma concentration (C trough ) ranged from 0.92‐fold to 1.15‐fold, indicating good predictive performance. The model quantitatively indicated the impact of cytochrome P450 ( CYP )3A4 abundance, hematocrit, and serum albumin levels, in addition to CYP 3A5 genotype status, on tacrolimus PK and associated variability. Age‐dependent change in tacrolimus trough concentration in pediatric patients was mainly attributed to the CYP 3A ontogeny profile. This study demonstrates the utility of PBPK modeling as a tool for mechanistic and quantitative assessment of the impact of patient physiological differences on observed large PK variability.

Morphine is commonly used for analgesia in the neonatal intensive care unit (NICU) despite having highly variable pharmacokinetics (PKs) between individual patients. The pharmacogenetic (PG) effect of variants at the loci of organic cation transporter 1 (OCT1) and UDP-glucuronosyltransferase 2B7 (UGT 2B7) on age-dependent morphine clearance were evaluated in a cohort of critically ill neonatal patients using an opportunistic sampling design. Our primary results demonstrate the significant influence of OCT1 genotype (P < 0.05) and gestational age (P ≤ 0.005) on morphine PKs. A physiologically based pharmacokinetic (PBPK) model for morphine that accounted for OCT1 ontogeny and PG effect in post-term neonates adequately described the clinically observed variability in morphine PKs. This study serves as a proof of concept for genotype-dependent drug transporter ontogeny in neonates.Morphine is widely used for management of perioperative pain and/or neonatal abstinence syndrome in the neonatal intensive care unit (NICU) of many hospitals. Wide interpatient variability in morphine exposure and response among neonates and small infants is a major limitation to morphine pharmacotherapy within these younger populations, making it difficult for clinicians to determine appropriate individualized dosage. Suboptimal dose titration is associated with both inadequate pain control in the case of underexposure, and often life-threatening side effects (primarily excessive sedation and respiratory depression) in the case of overexposure. 1,2 The variability in exposure and response to morphine observed in patients has been presumed to correlate with differences in morphine pharmacokinetics (PKs). 3,4 In young patients, the factors underlying morphine PKs are complex due to increase in body size (growth), pharmacogenetic (PG) effects, age-related physiological differences, and/or disease condition/progress. Especially in neonatal and small infant patients, the ontogeny of metabolic enzyme and drug transporter expression should

Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood‐flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP‐glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood‐flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age‐dependent factors into the pediatric system platform resulted in reasonable prediction for an age‐dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age‐dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood‐flow.

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Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinically important drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Knowledge of OCT1 protein expression in children, especially neonates and small infants, is currently very limited. Here, we report on the characterization of OCT1 protein expression in neonatal, infant, and pediatric liver samples performed using immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal days 1 and 2. This youngest group showed significantly lower OCT1 expression normalized by glyceraldehyde-6-phosphate dehydrogenase (values given as means ± S.D. in arbitrary units; 0.03 ± 0.02, n = 7) compared with samples from patients aged 3 to 4 weeks (0.08 ± 0.03, n = 5, P < 0.01), 3 to 6 months (0.23 ± 0.15, n = 7, P < 0.01), 11 months to 1 year (0.42 ± 0.32, n = 6, P < 0.01), and 8 to 12 years (1.00 ± 0.44, n = 7, P < 0.01). These data demonstrate an age-dependent increase in OCT1 expression from birth up to 8 to 12 years of age, and the findings of this study contribute to the understanding of OCT1 functional capacity and its effect upon the disposition of OCT1 substrates in neonates and small infants.

Autophagy contributes to cellular homeostasis through metabolite recycling and degradation of cytotoxic protein aggregates and damaged organelles. Although recent studies have established that the requirement for basal autophagy is largely tissue specific, the importance of autophagy for alveolar epithelial cell homeostasis remains an important knowledge gap. In the present study we generated two mouse models, with > 90% or > 50% recombination at the Atg5 locus in the distal respiratory epithelium, to assess the effect of dose-dependent decreases in autophagy on alveolar homeostasis. A 90% decrease in autophagy was well tolerated in young adult mice but resulted in alveolar septal thickening and altered lung mechanics in aged animals, consistent with accumulation of damage over time. By comparison, a 50% decrease in autophagy had no effect on alveolar structure or function throughout the murine life span, indicating that basal autophagy in this compartment exceeds that required for homeostasis. A 50% decrease in autophagy in the bronchoalveolar epithelium significantly attenuated influenza A/H3N2 viral replication, leading to improved lung structure and function and reduced morbidity and mortality after infection. The reserve of autophagic capacity in the alveolar epithelium may provide a niche for replication of influenza A virus.

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