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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.

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.

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 × mean life‐span potential (MLP) or CL × brain weight, CL s 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 CL s of biliary excreted drugs were predicted in humans. Predicted CL s 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. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1908–1914, 2002

Recent advances in in vitro metabolism methods have led to an improved ability to predict clinically relevant metabolic drug-drug interactions. To address the relationships of in vitro metabolism data and in vivo metabolism outcomes, the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research, Food and Drug Administration, evaluated a number of recently approved new drug applications. The goal of these evaluations was to determine the contribution of in vitro metabolism data in (1) predicting in vivo drug-drug interactions, (2) determining the need to conduct an in vivo drug-drug interaction study, and (3) incorporating findings into drug product labeling. Ten cases are presented in this article. They fall into two major groups: (1) in vitro data were predictive of in vivo results, and (2) in vitro data were not predictive of in vivo results. Discussion of these cases highlights factors limiting predictability of in vivo metabolic interactions from in vitro metabolism data. The integration of these findings into drug product labeling is also discussed.

Buspirone is an anxiolytic drug given at a dosage of 15 mg/day. The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors. Following a oral dose of buspirone 20 mg, the drug is rapidly absorbed. The mean peak plasma concentration (Cmax) is approximately 2.5 micrograms/L, and the time to reach the peak is under 1 hour. The absolute bioavailability of buspirone is approximately 4%. Buspirone is extensively metabolised. One of the major metabolites of buspirone is 1-pyrimidinylpiperazine (1-PP), which may contribute to the pharmacological activity of buspirone. Buspirone has a volume of distribution of 5.3 L/kg, a systemic clearance of about 1.7 L/h/kg, an elimination half-life of about 2.5 hours and the pharmacokinetics are linear over the dose range 10 to 40 mg. After multiple-dose administration of buspirone 10 mg/day for 9 days, there was no accumulation of either parent compound or metabolite (1-PP). Administration with food increased the Cmax and area under the plasma concentration-time curve (AUC) of buspirone 2-fold. After a single 20 mg dose, the Cmax and AUC increased 2-fold in patients with renal impairment as compared with healthy volunteers. The Cmax and AUC were 15-fold higher for the same dose in patients with hepatic impairment compared with healthy individuals. The half-life of buspirone in patients with hepatic impairment was twice that in healthy individuals. The pharmacokinetics of buspirone were not affected by age or gender. Coadministration of buspirone with verapamil, diltiazem, erythromycin and itraconazole substantially increased the plasma concentration of buspirone, whereas cimetidine and alprazolam had negligible effects. Rifampicin (rifampin) decreased the plasma concentrations of buspirone almost 10-fold.

Publisher Summary This chapter discusses the role of the Food and Drug Administration (FDA) in guiding drug development. The FDA guides drug development in many different ways such as (1) by interpreting laws, rules, and regulations; (2) by disseminating policy statements that may otherwise be vague or unclear; (3) by providing advice and sharing experiences and expertise in face-to-face meetings and through written agreements and letters; (4) by domestic and international guidances; (5) by planned telephone conferences and/or scheduled videoconferences; and (6) by the FDA web site. The FDA also guides drug development by holding closed or open advisory committee meetings. These meetings facilitate the regulatory review and FDA approval process by bringing together external experts to assess data, recommend need for new studies, and address specific questions formulated by the FDA to help resolve scientific or clinical problems related to the drug development process or a specific product approval. The most widespread, effective, and important way that the FDA communicates with sponsors and guides drug development is through guidances issued either by the FDA or by the International Conference on Harmonization (ICH). The FDA should take the lead in developing a national Critical Path Opportunities List to bring concrete focus to these tasks and prepare for the challenges in drug development in the future.

The views expressed in this article are those of the author’s and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.1. INTRODUCTIONThis chapter deals with some of the regulatory issues that need to be considered at the time of developing a drug with chiral center(s). Before we discuss regulatory issues in developing chiral drugs, a brief discussion of drug development and its regulatory process is warranted.

Although women have been included in drug development in numbers predicted by their disease prevalence whenever this has been examined, the conduct of gender-specific analysis has become standard only in the last decade; these are often referenced in labeling. Pharmacokinetic (PK) differences, by far the most common known gender differences, are readily assessed because gender-specific PK data are now regularly obtained. The chapter discusses the current status of participation of women in clinical trials of new medical products and gender differences and the current status of clinical pharmacology/biopharmaceutic studies of new drugs and gender differences The exclusion of women from early trials in life-threatening conditions because of their childbearing potential was barred by regulation in 1993. During the last 2 decades, the FDA has encouraged inclusion in clinical trials of a reasonable representation of both genders, of people with ethnic profiles similar to the population that will be using the product, and of people at the extremes of age. Current practice should ensure the detection of large gender differences in response, but subtle differences may be undetected until they are specifically sought. The profound gender effects of the selective serotonin reuptake inhibitor (SSRI) antidepressants on sexual function in women were significantly underestimated for years because usual clinical trials do not assess this function well. The greater susceptibility of women to drugs that cause TdP arrhythmias also took many years to become recognized, as did the potential of CYP3A inducers to render oral contraceptives ineffective.