Chie Emoto

Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic haematopoietic cell transplantation (HCT). A recently proposed therapeutic range of 0.15–0.6 μg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for paediatric patients.Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 paediatric and young adult patients (median age 6.4 y; range 0.28–21.4 y) with nonmalignant disorders undergoing HCT. PK/PD analyses were performed using nonlinear mixed effects modelling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches.Results: A one‐compartment model with sequential zero‐ and first‐order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70 kg) and volume of distribution (17.4 L/70 kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory E_max model best characterized the relationship between alemtuzumab concentration and ALC. E_max and EC₅₀ were estimated as 1.18 × 10³/μL and 0.045 μg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated optimal target achieving dose as allometry‐based dose of 18 mg × (weight/70)^0.75 or body surface area‐based dose of 10 mg/m², divided over 3 days, with a potential individualized top‐up dose; both of which yielded similar results.Conclusion: An allometry‐ or body surface area‐based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

We have previously reported the influences of OCT1 ontogeny and genetic variation on morphine clearance in neonatal and pediatric patients. In the latter study, plasma morphine‐glucuronide levels correlated with patient genotype for the rs4793665 single‐nucleotide polymorphism (SNP) at the locus of MRP3, an efflux transporter of morphine glucuronides between hepatocytes and circulating blood. The link between MRP3 activity and overall morphine clearance has not been thoroughly investigated however, and the developmental profile of hepatic MRP3 protein expression remains thinly defined between neonates and adults. In the current study, previously determined morphine clearance values for neonatal (24‐58 weeks postmenstrual age, N = 57) and pediatric (5‐16 years, n = 85) patients were reanalyzed for correlation to the SNP genotype of patient rs4793665. Among OCT1 wild‐type patients, pediatric morphine clearance showed a significant decreasing trend by MRP3 genotypes in the order of CC > CT > TT (P = .014), whereas for neonates, an identical but nonsignificant trend was observed. Pharmacogenetic differences in MRP3 and OCT1 ontogeny were evaluated by Western blot of hepatic membrane fractions from 50 subjects aged 1 day postnatal to 33 years old. Hepatic MRP3 protein level did not vary by rs4793665 genotype, and followed an atypical developmental pattern of increase up to 1‐2 years of age, thereafter decreasing during preadolescence before increasing again to adult levels at maturity (17‐33 years). By comparison, OCT1 expression was significantly decreased in OCT1 *1/*3 genotyped patients older than 1 year and followed a trajectory consistent with prior studies. Our results suggest that consideration of MRP3 pharmacogenetics and ontogeny may aid in identifying pediatric patients having different/atypical morphine requirements.

Aims: Fanconi anaemia (FA) is a rare disorder characterized by progressive bone marrow failure that requires haematopoietic cell transplantation (HCT). Busulfan is used in conditioning regimens prior to HCT. Doses used in non‐FA patients cause life‐threatening toxicities in FA patients and data on busulfan pharmacokinetics (PK) in this population are limited. This study characterized busulfan PK in paediatric FA patients using population PK modelling and evaluated the effect of body composition on steady‐state concentrations (C_ss).Methods: A total of 200 busulfan plasma concentrations in 29 FA patients from a recent study (Clinicaltrials.gov; NCT01082133) were available for population PK modelling. The effect of different body size‐scaled doses and body compositions on C_ss was investigated using population PK modelling.Results: Fat free mass (FFM) was identified as the best size descriptor in a two‐compartment busulfan PK model in FA patients. Conventional dosing, based on an amount of busulfan per kilogram of total body mass, resulted in higher C_ss in FA patients with higher body mass index (BMI). A newly proposed FFM‐based dosing strategy would eliminate the observed trend of higher concentrations in high BMI patients, and achieve consistent C_ss across a wide BMI spectrum.Conclusions: This is the first study to describe the population PK of busulfan in paediatric FA patients. The proposed model will facilitate PK model‐informed precision dosing. FFM‐based dosing is expected to improve the probability of achieving target C_ss, particularly in obese patients, while minimizing the risk of overdosing.

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 (UGT2B7) 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 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.

Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration‐time profiles in healthy adults and diseased patients. The implementation of developmental changes in both renal and non‐renal elimination pathways to the pediatric model improved the predictability of vancomycin clearance. Simulated PK profiles with a 50% decrease in cardiac output (peak plasma concentration (C_max), 59.9 ng/mL) were similar to those observed in patients before bypass surgery (C_max, 55.1 ng/mL). The PBPK modeling of vancomycin demonstrated its potential to provide mechanistic insights into the altered disposition observed in patients who have changes in multiple physiological factors.