Quantitative prediction of CYP3A-mediated drug-drug interactions by correctly estimating fraction metabolized using human liver chimeric mice.

BACKGROUND AND PURPOSE: Fraction metabolized (fm ) and fraction transported (ft ) are important for understanding drug-drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo fm due to inability to reflect the ft by efflux transporters (ft,efflux ). This study demonstrates how CYP3A-mediated DDI for CYP3A/P-gp substrates can be predicted using Hu-PXB mice as human liver chimeric mice. EXPERIMENTAL APPROACH: For estimating human in vitro fm by CYP3A enzyme (fm,CYP3A,in vitro ), six drugs, including CYP3A/P-gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated fm,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo fm,CYP3A (fm,CYP3A,in vivo ), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated fm,CYP3A,in vivo using the change of total clearance (CLtotal ). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu-PXB and SCID mice with or without ketoconazole. We calculated the change of CLtotal caused by ketoconazole. We compared the CLtotal change in humans with that in Hu-PXB and SCID mice. KEY RESULTS: The fm,CYP3A,in vitro was overestimated compared to the fm,CYP3A,in vivo . Hu-PXB mice showed much better correlation in the change of CLtotal with humans (R2 = 0.95) compared to SCID mice (R2 = 0.0058). CONCLUSIONS AND IMPLICATIONS: CYP3A-mediated DDI can be predicted by correctly estimating human fm,CYP3A,in vivo using Hu-PXB mice. These mice could be useful predicting hepatic fm and ft,efflux .

Development and Verification of a Japanese Pediatric Physiologically Based Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or Renal Excretion.

Physiologically based pharmacokinetic (PBPK) models are useful in bridging drug exposure in different ethnic groups, and there is increasing regulatory application of this approach in adults. Reported pediatric PBPK models tend to focus on the North European population, with few examples in other ethnic groups. This study describes the development and verification of a Japanese pediatric PBPK population. The development of the model was based on the existing North European pediatric population. Japanese systems and clinical data were collated from public databases and the literature, and the underlying demographics and equations were optimized so that physiological outputs represented the Japanese pediatric population. The model was tested using 14 different small molecule drugs, eliminated by a variety of pathways, including cytochrome P450 3A4 (CYP3A4) metabolism and renal excretion. Given the limitations of the clinical data, the overall performance of the model was good, with 44/62 predictions for PK parameters (area under the plasma drug concentration-time curve, AUC; maximum serum concentration, Cmax ; clearance, CL) being within 0.8- to 1.25-fold, 56/62 within 0.67- to 1.5-fold, and 61/62 within 0.5- to 2.0-fold of the observed values. Specific results for the 5 CYP3A4 substrates showed 20/31 cases were predicted within 0.8- to 1.25-fold, 27/31 within 0.67- to 1.5-fold, and all were within 0.5- to 2.0-fold of the observed values. Given the increased regulatory use of pediatric PBPK in drug development, expanding these models to other ethnic groups are important. Considering qualifying these models based on the context of use, there is a need to expand on the current research to include a larger range of drugs with different elimination pathways. Collaboration among academic, industry, model providers, and regulators will facilitate further development.

Cytochrome P450 enzymes in the pediatric population: Connecting knowledge on P450 expression with pediatric pharmacokinetics.

Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by deconvolution of in vivo pharmacokinetic data observed in pediatric populations. The age-dependent changes in P450 enzyme expression can be important determinants of drug disposition in childhood, in addition to the changes in body size and the other physiological parameters, and effects of pharmacogenetics and disease on organ functions. As a tool incorporating drug-specific and body-specific factors, physiologically-based pharmacokinetic (PBPK) models have become increasingly used to characterize and explore mechanistic insights into drug disposition. Thus, PBPK models can be a bridge between findings from basic science and utilization in predictive science. Pediatric PBPK models incorporate additional system specific information on developmental physiology and ontogeny and have been used to predict pharmacokinetic parameters from preterm neonates onwards. These models have been advocated by regulatory authorities in order to support pediatric clinical trials. The purpose of this chapter is to highlight accumulated knowledge and findings from basic research focusing on P450 enzymes, as well as the current status and future challenges of expanding the utilization of pediatric PBPK modeling.

Optimal Teicoplanin Dosing Regimen in Neonates and Children Developed by Leveraging Real-World Clinical Information.

BACKGROUND: Teicoplanin is a glycopeptide antibiotic used for the treatment of methicillin-resistant Staphylococcus aureus infections. To ensure successful target attainment, therapeutic drug monitoring-informed dosage adjustment is recommended. However, it relies on the experience of the clinician and the frequency of drug measurements. This study aimed to design a new optimal dosing regimen of teicoplanin with a maintenance dosing strategy for neonates and children based on their physiological characteristics. METHODS: Data from teicoplanin-treated patients (n = 214) were collected from electronic medical records. Covariate analyses were performed using population pharmacokinetic (PK) modeling with 399 serum teicoplanin concentrations from 48 neonates and 166 children. Multiple PK simulations were conducted to explore optimal dosing regimens that would allow control of the trough concentration to the target of 15-30 mg/L quicker than the current standard regimen. RESULTS: Allometrically scaled body weight, postmenstrual age (PMA), renal function, and serum albumin were implemented as substantial covariates for teicoplanin clearance in a two-compartment PK model. Covariate analyses and comprehensive simulation assessments recommended the following modifications to the current regimen: (1) decreased dose for premature babies (PMA ≤28 weeks), (2) decreased dose for children with renal dysfunction, and (3) increased dose for children (0.5-11 years) with an estimated glomerular filtration rate of ≥90 mL/min/1.73 m2. CONCLUSIONS: This study leverages real-world clinical information and proposes new optimal dosing regimens for teicoplanin in neonates and children through PK modeling and simulation analyses, taking into account the age, including PMA, and renal function of patients.

Model-informed precision dosing for alemtuzumab in paediatric and young adult patients undergoing allogeneic haematopoietic cell transplantation.

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 Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax 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.

A prospective pilot study of a novel alemtuzumab target concentration intervention strategy.

Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15-0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15-0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5-0.6 mcg/kg divided over days -14 to -12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day -5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual "top-up" dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.

Feasibility of physiologically based pharmacokinetic simulations for assessing pediatric patients after accidental drug ingestion: A case study of a 1.4-year-old girl who ingested alprazolam.

The accidental ingestion of drugs is a common concern, especially in the case of young children. A physiologically based pharmacokinetic (PBPK) model that implements the age-dependent size growth and ontogeny of organ functions can be used to predict the concentration-time profiles of drugs in the pediatric population. In this study, the feasibility of using a PBPK model for predicting the amount of drug accidentally swallowed by a child was assessed based on a case study in an infant. Alprazolam was the drug involved in the current case. The developed PBPK model of alprazolam was first evaluated using pharmacokinetic data obtained in healthy adult male volunteers. Then, it was adapted for application to virtual Japanese pediatric subjects having the same demographic information as the infant of interest. The pharmacokinetic data observed in the infant fell within the range of the 5th and 95th percentiles of the pharmacokinetic simulations after administration of 0.4 mg alprazolam (equivalent to one tablet) in the panel of virtual infants. PBPK simulations could provide estimates of the amount accidentally ingested by a child and also give mechanistic insights into the observed drug concentrations. The current study demonstrates the potential clinical utility of PBPK modeling.

Teicoplanin physiologically based pharmacokinetic modeling offers a quantitative assessment of a theoretical influence of serum albumin and renal function on its disposition.

PURPOSE: Variability in teicoplanin pharmacokinetics has been explained by multiple factors such as body weight, renal function, and serum albumin level. To improve mechanistic understanding of the causes of variability, a physiologically based pharmacokinetic (PBPK) model can be used as a systematic platform. In this study, a PBPK model of teicoplanin was developed to quantitatively assess the effects of physiological changes due to disease status using virtual populations. METHODS: Predictive performance of the models was evaluated by comparing simulated and observed concentration-time profiles of teicoplanin. Subsequently, sensitivity analyses were conducted to identify potential factors contributing to individual differences in teicoplanin PK. RESULTS: The developed PBPK model generated concentration-time profiles that were comparable to clinical observations in healthy adults, including Caucasians and Japanese, and after single-dose and multiple-dose administration. The predicted PK parameters (i.e., Cmax, AUC, clearance) were within a two-fold range of the observed data in patients with renal impairments as well as healthy adults. Changes in total and unbound teicoplanin concentrations at 72 h, after various dosing regimens (tested 4-14 mg/kg q12h for three doses as a loading dose and then 4-14 mg/kg daily as a maintenance dose), were sensitive to renal function and serum albumin concentrations. CONCLUSION: The PBPK model of teicoplanin provides mechanistic insight into the factors altering its disposition and allows assessments of the theoretical and quantitative impact of individual changes in physiological parameters on its PK even when an actual assessment with adequate sample sizes of patients is challenging.

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas.

PURPOSE: Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. METHODS: Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m2/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. RESULTS: Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. CONCLUSION: To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.

Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches.

Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first-line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

Influence of MRP3 Genetics and Hepatic Expression Ontogeny for Morphine Disposition in Neonatal and Pediatric Patients.

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.

Population pharmacokinetic modelling of busulfan and the influence of body composition in paediatric Fanconi anaemia patients.

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 (Css ). 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 Css 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 Css 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 Css 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 Css , particularly in obese patients, while minimizing the risk of overdosing.

Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients.

Chronic intrauterine exposure to psychoactive drugs often results in neonatal abstinence syndrome (NAS). NAS is the symptomatic drug withdrawal in newborns that generally occurs after in utero chronic opioid exposure. Methadone is an opioid analgesic commonly prescribed for pharmacologic management of NAS. It exhibits high pharmacokinetic (PK) variability. The current study used physiologically based PK modeling to predict the PK profile of methadone in 20 newborns treated for NAS. The physiologically based PK simulations adequately predicted the PK profile of the clinical data for 45% of the patients. Sensitivity analyses were conducted to explore contributing factors to methadone PK variability. The data suggest that P450 enzymatic activity impacts the clearance of methadone in virtual adults and neonates, while the contribution of cardiac output may be negligible. Understanding maturational and/or pharmacogenetic changes in cytochrome P450 enzymatic activity may further explain the large PK variability of methadone in newborns with NAS and will help individualized treatment.

Adult and infant pharmacokinetic profiling of dihydrocodeine using physiologically based pharmacokinetic modeling.

We previously analysed the serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression after being prescribed dihydrocodeine phosphate 2.0 mg/day divided t.i.d. for 2 days. The purpose was to develop a full physiologically based pharmacokinetic (PBPK) model that could account for these and other drug monitoring results. Based on experiments in Caco-2 cell monolayers, the effective permeability of dihydrocodeine in human jejunum was established as 1.28 × 10-4 cm/s. The in vitro Vmax /Km values for dihydrocodeine demethylation mediated by recombinant cytochrome P450 2D6 and 3A4 were 0.19 and 0.066 µl/min/pmol, respectively, and for dihydrocodeine 6-O-glucuronidation mediated by recombinant UGT2B4 and 2B7, the Vmax /Km values were 0.14 and 0.22 µl/min/mg protein, respectively. Renal clearance was calculated as 5.37 L/h on the total clearance value multiplied by the fraction recovered in urine. The reported plasma concentration-time profiles of dihydrocodeine after intravenous administration in healthy volunteers were used to adjust the tissue partitioning ratios. The developed model simulated the pharmacokinetic profiles of dihydrocodeine after single and multiple oral administrations reasonably well in the same population. Subsequently, the validated model was used to simulate pharmacokinetic profiles for five pediatric cases, including the 1-month-old Japanese boy and a 14-year-old Japanese girl who took an overdose of dihydrocodeine phosphate (37 mg). The simulated pharmacokinetic profiles for five virtual pediatric subjects matching the age, gender, and P450 2D6 phenotype of each case approximately reflected the observed values. These results suggested that our dihydrocodeine PBPK model reproduced the results of clinical cases reasonably well for subjects.

Busulfan Pharmacokinetics and Precision Dosing: Are Patients with Fanconi Anemia Different?

It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA), who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy-only conditioning, we replaced the single dose of total-body irradiation with BU at initial doses of 0.8 to 1.0 mg/kg and 0.6 to 0.8 mg/kg given i.v. every 12 hours for 4 doses. Patients received the first dose of i.v. busulfan on day -8, and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hours, 2 hours and 15 minutes, and 4, 5, 6, and 8 hours from the start of infusion. The remaining 3 doses of BU were given on days -7 and -6. Thirty-seven patients with available BU PK data with a median age of 9.2 years (range, 4.3 to 44 years) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort, a strong correlation between BU clearance and weight supports current practice of per kilogram dosing. However, not surprisingly, we show that the disease (ie, host) sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high-risk population. On the basis of our results, we propose an optimal BU concentration at steady-state level of ≤350 ng/mL (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. To our knowledge, this is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing an optimal BU target cutoff to achieve stable donor engraftment while avoiding excessive toxicity.

Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus.

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

A Theoretical Physiologically-Based Pharmacokinetic Approach to Ascertain Covariates Explaining the Large Interpatient Variability in Tacrolimus Disposition.

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 (Cmax ), 0-12-hour area under the concentration-time curve (AUC0-12 hour ), and trough plasma concentration (Ctrough ) 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 CYP3A5 genotype status, on tacrolimus PK and associated variability. Age-dependent change in tacrolimus trough concentration in pediatric patients was mainly attributed to the CYP3A 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.

Influence of OCT1 Ontogeny and Genetic Variation on Morphine Disposition in Critically Ill Neonates: Lessons From PBPK Modeling and Clinical Study.

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.