This article is available online at http://dmd.aspetjournals.org ABSTRACT:Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.Drug-drug interactions can lead to severe side effects and have resulted in early termination of development, refusal of approval, severe prescribing restrictions, and withdrawal of drugs from the market. Regulators, including the U.S. Food and Drug Administration (FDA 1 ) have therefore issued guidances for in vitro and in vivo drug interaction studies to be conducted during development. These guidances, however, do not address the specific designs of the studies, and there is a desire by regulatory authorities to harmonize approaches and study designs to allow for a better assessment and comparison of different drugs. In addition, the existing guidances cover mainly cytochrome P450 (P450)-mediated drug interactions and the importance of other mechanisms, such as transporters, has been recognized only recently. To address these issues, workshops have been held in

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.

BackgroundBAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia.ObjectivesTo assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.Patients/MethodsThis 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses.ResultsBAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ∼ 19 h (vs. ∼ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed.ConclusionsThis phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.

Prophylaxis with BAY 81-8973 using individualized prophylaxis regimens of 2× per week, 3× per week and every-other-day infusions was efficacious in prevention and treatment of bleeds in children with severe haemophilia A. Treatment with BAY 81-8973 was well tolerated.

Introduction BAY 81‐8973 is a full‐length recombinant factor VIII (FVIII) with the same primary amino acid sequence as sucrose‐formulated recombinant FVIII (rFVIII‐FS) but is produced with advanced manufacturing technologies. Aim To analyse the pharmacokinetics (PK) of BAY 81‐8973 after single and multiple dosing across different age and ethnic groups in the LEOPOLD clinical trial programme. Methods The LEOPOLD trials enrolled patients with severe haemophilia A aged 12–65 years (LEOPOLD I and II) or ≤12 years (LEOPOLD Kids) with ≥150 (LEOPOLD I and II) or ≥50 (LEOPOLD Kids) exposure days to any FVIII product and no history of FVIII inhibitors. PK were assessed using chromogenic and one‐stage assays (only chromogenic assay for LEOPOLD Kids) after a single 50‐IU kg−1 dose of BAY 81‐8973 and, in a subset of patients in LEOPOLD I, after repeated dosing. Pharmacokinetic analyses were also performed based on age (18 to 65, 12 to <18, 6 to <12 and <6 years) and ethnicity (Asian and non‐Asian). Results Pharmacokinetic assessments in the LEOPOLD I trial showed non‐inferiority of BAY 81‐8973 vs. rFVIII‐FS. The PK of BAY 81‐8973 were comparable after single and multiple dosing. Age‐based analysis in the three trials showed that plasma concentrations were slightly lower for children, but similar for adolescents compared with adults. Pharmacokinetic results were similar in the different ethnic groups. Conclusions Results of the LEOPOLD trials show that the BAY 81‐8973 pharmacokinetic profile is non‐inferior to rFVIII‐FS. Similar BAY 81‐8973 pharmacokinetic values were observed following single and repeated dosing and across ethnic groups.

BackgroundBAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) for the treatment of hemophilia A.ObjectiveThe aim of this study was to compare the pharmacokinetic (PK) profile of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM)Patients/MethodsIn this phase I, open-label, crossover study, men aged 18–65 years with severe hemophilia A and ≥150 exposure days to FVIII were randomized to receive a single intravenous infusion of 50 IU/kg BAY 81-8973 or rAHF-PFM, followed by crossover to a single infusion of the other treatment. FVIII levels were measured in plasma over 48 h using one-stage and chromogenic assays. PK parameters, including area under the curve from time zero to the last data point (AUClast; primary outcome) and half-life (t ½) were calculated. A population PK model was developed to simulate various treatment scenarios.ResultsEighteen patients were randomized and analyzed. Using both assays, geometric mean (coefficient of variation [%CV]) AUClast was significantly higher, and t ½ was significantly longer, for BAY 81-8973 versus rAHF-PFM (one-stage, AUClast: 1660 IU·h/dL [29.4] vs. 1310 IU·h/dL [29.0], p < 0.0001; one-stage, t ½: 14.5 [25.7] vs. 11.7 h [27.3], p < 0.0001). Simulations showed that median time to 1 IU/dL was approximately 27% longer for BAY 81-8973 versus rAHF-PFM over doses of 25–50 IU/kg; plasma levels >1 IU/dL could be maintained with 14.4 IU/kg BAY 81-8973 or 39.1 IU/kg rAHF-PFM 3×/week.ConclusionsBAY 81-8973 showed a superior PK profile versus rAHF-PFM. The same FVIII trough threshold level could be achieved with lower doses of BAY 81-8973 versus rAHF-PFM.ClinicalTrials.gov: NCT02483208.

Introduction:The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials. Aim: The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life. Methods: The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1-61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL À1 for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold. Results: In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples. Conclusions: It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients.