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.

Abstract. The Conference Report of the 3rd AAPS/FDA Bioanalytical Workshop (Crystal City III) endorsed the concept that assay methods supporting bioanalytical data in submissions must demonstrate assay reproducibility by using incurred samples. The present Workshop was convened to provide a forum for discussion and consensus building about incurred sample assay reproducibility for both nonclinical and clinical studies. Information about current regulatory perspectives on incurred sample reanalysis (ISR) was presented, implications of ISR for both large and small molecules were discussed, and the steering committee put forth recommendations for performing ISR. These recommendations from the Workshop, along with the subsequent evolution of approaches leading to a robust ISR program, may be used by scientists performing bioanalytical assays for regulated studies to provide additional confirmation of assay reproducibility for incurred samples.

A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.