Wiles JR, Isemann B, Mizuno T, Tabangin ME, Ward LP, Akinbi H, Vinks AA. Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study. J Pediatr. 2015 Dec;167(6):1214-20 e3.
This study characterized the population pharmacokinetic (PK) of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome (NAS) and developed a PK model towards an evidence-based treatment protocol. Researchers assessed concentrations of methadone and its metabolites via high performance liquid chromatography-tandem mass spectrometry from dried blood spots. They performed population PK analysis to determine the volume of distribution and clearance of oral methadone. Researchers simulated methadone plasma concentration-time profiles from the deduced PK model to optimize the dosing regimen. The study developed a new dosing and expedited weaning protocol for patients requiring pharmacologic treatment of NAS. The proposed dosing regimen may reduce the cumulative dose of opioid and shorten the length of hospitalization and is currently being prospectively evaluated.
Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24.
Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 non-expressers (poor metabolizers), possibly delaying achievement of target blood concentrations. In this study, we summarized evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).
Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, Hirsch R, Teusink A, Lazear D, Lane A, Myers KC, Dandoy CE, Davies SM. Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2016 Feb;22(2):307-15.
Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplant (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. Sixty one percent of treated patients had complete resolution of TMA, and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared to untreated patients (56% versus 9%, p=0.003). Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined inter-individual differences in PK parameters. Our eculizumab dosing algorithm accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
Emoto C, Fukuda T, Venkatasubramanian R, Vinks AA. The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically-based pharmacokinetic model. Br J Clin Pharmacol. 2015 Dec;80(6):1438-46.
Sirolimus is an mTOR inhibitor metabolized by CYP3A4 and CYP3A5. Reported effects of CYP3A5 polymorphisms on sirolimus pharmacokinetics (PK) have shown unexplained discrepancies across studies. We quantitatively assessed the effect of CYP3A5*3 status on sirolimus PK by in vitro assessment and simulation using a physiologically-based PK (PBPK) model. In addition, we explored designs for an adequately powered pharmacogenetic association study. The PBPK model predicted a small CYP3A5*3 effect on simulated sirolimus PK profiles. A subsequent power analysis based on these findings indicated that at least 80 subjects in an enrichment design, 40 CYP3A5 expressers and 40 non-expressers, is required to detect a significant difference in the predicted trough concentrations at 1 month of therapy (P < 0.05, 80% power). This study suggests that CYP3A5 contribution to sirolimus metabolism is much smaller than that of CYP3A4. The result of inadequate sample size could explain observed discrepancies across published studies. PBPK model simulations allowed mechanism-based evaluation of the effects of CYP3A5 genotype on sirolimus PK and provide preliminary data for the design of an adequately powered prospective study.
Dong M, McGann PT, Mizuno T, Ware RE, Vinks AA. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Br J Clin Pharmacol. 2016 Apr;81(4):742-52.
Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Researchers analyzed pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) by using non-linear mixed effects modeling (Nonmem 7.2). The study evaluated A D-optimal sampling strategy to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, to achieve clinical benefits at MTD more quickly.