Drug-Drug Interaction Studies of Methadone and Antiviral Drugs: Lessons Learned.

Different views appear in the literature on the extent of specific cytochrome P450 (CYP) involvement in methadone metabolism. The aim of this work is to leverage knowledge from drug-drug interaction (DDI) studies in new drug applications between methadone and antiviral medications to better understand methadone disposition and to inform design of future DDI studies with methadone. A database of DDI studies between all FDA-approved human immunodeficiency virus and hepatitis C virus medications and methadone was constructed. The database contains data from 29 DDI studies. Sixteen of the 29 studies had statistically significant changes in methadone area under the concentration-time curve. Methadone exposure was either decreased or unchanged when it was coadministered with weak to strong CYP3A inhibitors or a moderate CYP3A4 inducer. Methadone exposure was reduced when it was coadministered with CYP2B6 inducers. The role of other enzymes (CYP2C9, CYP2C19, and CYP2D6) cannot be fully elucidated from these studies. In conclusion, CYP2B6 plays a prominent role in methadone metabolism, although methadone exposure is not sensitive to CYP3A perturbation. In designing methadone DDI studies, (1) measuring R- and S-methadone is more informative than measuring total methadone, and (2) CYP2B6 genotyping of subjects enrolled in methadone DDI studies should be considered. Finally, there is a need for the development of predictive models to determine the influence of medications on methadone disposition.

Dosage Considerations for Canakinumab in Children With Periodic Fever Syndromes.

Periodic fever syndromes are a group of rare diseases with a highly variable onset, yet limited treatment options are available for children at an early age. Canakinumab has been approved to treat patients with cryopyrin-associated periodic syndrome, a periodic fever syndrome, and systemic juvenile systemic arthritis, with age cutoffs of 4 years and 2 years, respectively. In 2016, the US Food and Drug Administration (FDA) approved canakinumab, without an age restriction, for the treatment of three conditions of periodic fever syndromes, including familial Mediterranean fever, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, and tumor necrosis factor receptor-associated periodic syndrome. This review discusses the pharmacokinetic (PK), efficacy, safety, and exposure-response relationship of canakinumab and provides the rationale for dosage recommendation in children younger than 2 years of age with the three conditions of periodic fever syndromes. The approval of canakinumab for these pediatric patients addresses a critical unmet medical need.

Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients.

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients < or = 12 kg should be dosed at 1.1 mg/kg and those > 12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

Interspecies scaling of biliary excreted drugs.

The objective of this study is to predict clearance of drugs in humans from animals which are excreted in the bile. Clearance (CL) of eight drugs known to be excreted in the bile were randomly selected from the literature. Scaling of CL was performed using at least three animal species. Using simple allometry, CL x mean life-span potential (MLP) or CL x brain weight, CLs of studied drugs were predicted in humans. The choice of one of the methods depended on the 'rule of exponents' as described by Mahmood and Balian. A 'correction factor' was calculated by adjusting bile flow rate based on the species body weight (bile flow = mL/day/kg body weight) or liver weight (bile flow = mL/day/kg liver weight). Using the 'rule of exponents' and combining it with the 'correction factor', the CLs of biliary excreted drugs were predicted in humans. Predicted CLs in humans from animals using simple allometry were several times higher for all eight drugs (% error [range] = 46-1703). Using the 'rule of exponents' and combining it with a 'correction factor' as described in this report provided a substantial improvement (% error [range] = 5-91) in the prediction of CL for biliary excreted drugs. The results of this study indicate that the CL of a biliary excreted drug may be overpredicted in humans and by applying the 'correction factor' employed here, the predictability of drug CL in humans from animal data may be significantly improved.