PMID- 31247117 OWN - NLM STAT- MEDLINE DCOM- 20200604 LR - 20200604 IS - 1532-6535 (Electronic) IS - 0009-9236 (Linking) VI - 106 IP - 6 DP - 2019 Dec TI - A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin. PG - 1398-1407 LID - 10.1002/cpt.1564 [doi] AB - A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance (CL(R) )), 100 mg sitagliptin (OAT3; CL(R) ), 500 mg metformin (several renal transporters; CL(R) ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (C(max) ) and CL(R) ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs in vivo. CI - (c) 2019 The Authors Clinical Pharmacology & Therapeutics (c) 2019 American Society for Clinical Pharmacology and Therapeutics. FAU - Trueck, Christina AU - Trueck C AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. FAU - Hsin, Chih-Hsuan AU - Hsin CH AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. FAU - Scherf-Clavel, Oliver AU - Scherf-Clavel O AD - Institute for Biomedical and Pharmaceutical Research, Nurnberg-Heroldsberg, Germany. FAU - Schaeffeler, Elke AU - Schaeffeler E AD - Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. AD - University of Tuebingen, Tuebingen, Germany. FAU - Lenssen, Rebekka AU - Lenssen R AD - Hospital Pharmacy, University Hospital Cologne, Cologne, Germany. FAU - Gazzaz, Malaz AU - Gazzaz M AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. AD - Department of Clinical Pharmacy, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia. FAU - Gersie, Marleen AU - Gersie M AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. FAU - Taubert, Max AU - Taubert M AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. FAU - Quasdorff, Maria AU - Quasdorff M AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. FAU - Schwab, Matthias AU - Schwab M AD - University of Tuebingen, Tuebingen, Germany. AD - Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany. AD - Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany. FAU - Kinzig, Martina AU - Kinzig M AD - Institute for Biomedical and Pharmaceutical Research, Nurnberg-Heroldsberg, Germany. FAU - Sorgel, Fritz AU - Sorgel F AD - Institute for Biomedical and Pharmaceutical Research, Nurnberg-Heroldsberg, Germany. AD - Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany. FAU - Stoffel, Marc S AU - Stoffel MS AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. FAU - Fuhr, Uwe AU - Fuhr U AD - University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany. LA - eng SI - ClinicalTrials.gov/NCT02743260 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190812 PL - United States TA - Clin Pharmacol Ther JT - Clinical pharmacology and therapeutics JID - 0372741 RN - 0 (ABCB1 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (Liver-Specific Organic Anion Transporter 1) RN - 0 (Octamer Transcription Factor-1) RN - 0 (Organic Anion Transport Protein 1) RN - 0 (Organic Anion Transporters) RN - 0 (Organic Anion Transporters, Sodium-Independent) RN - 0 (Organophosphonates) RN - 0 (POU2F1 protein, human) RN - 0 (Quinolines) RN - 0 (SLCO1B1 protein, human) RN - 0 (SLCO4C1 protein, human) RN - 0 (organic anion transport protein 3) RN - 73K4184T59 (Digoxin) RN - 9100L32L2N (Metformin) RN - JAC85A2161 (Adenine) RN - M5681Q5F9P (pitavastatin) RN - TS63EW8X6F (Sitagliptin Phosphate) RN - U6Q8Z01514 (adefovir dipivoxil) SB - IM MH - ATP Binding Cassette Transporter, Subfamily B/genetics/metabolism MH - Adenine/*analogs & derivatives/pharmacokinetics MH - Adult MH - Digoxin/*pharmacokinetics MH - Drug Interactions MH - Female MH - Genotype MH - Healthy Volunteers MH - Humans MH - Liver-Specific Organic Anion Transporter 1/genetics/metabolism MH - Male MH - Metformin/*pharmacokinetics MH - Middle Aged MH - Octamer Transcription Factor-1/genetics/metabolism MH - Organic Anion Transport Protein 1/genetics/metabolism MH - Organic Anion Transporters/genetics/metabolism MH - Organic Anion Transporters, Sodium-Independent/genetics/metabolism MH - Organophosphonates/*pharmacokinetics MH - Quinolines/*pharmacokinetics MH - Sitagliptin Phosphate/*pharmacokinetics EDAT- 2019/06/28 06:00 MHDA- 2020/06/05 06:00 CRDT- 2019/06/28 06:00 PHST- 2019/04/09 00:00 [received] PHST- 2019/06/19 00:00 [accepted] PHST- 2019/06/28 06:00 [pubmed] PHST- 2020/06/05 06:00 [medline] PHST- 2019/06/28 06:00 [entrez] AID - 10.1002/cpt.1564 [doi] PST - ppublish SO - Clin Pharmacol Ther. 2019 Dec;106(6):1398-1407. doi: 10.1002/cpt.1564. Epub 2019 Aug 12.