Clarithromycin, Midazolam, and Digoxin: Application of PBPK Modeling to Gain New Insights into Drug-Drug Interactions and Co-medication Regimens.
Clarithromycin is a substrate and mechanism-based inhibitor of cytochrome P450 (CYP) 3A4 as well as a substrate and competitive inhibitor of P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATP) 1B1 and 1B3. Administered concomitantly, clarithromycin causes drug-drug interactions (DDI) with the victim drugs midazolam (CYP3A4 substrate) and digoxin (P-gp substrate). The objective of the presented study was to build a physiologically based pharmacokinetic (PBPK) DDI model for clarithromycin, midazolam, and digoxin and to exemplify dosing adjustments under clarithromycin co-treatment. The PBPK model development included an extensive literature search for representative PK studies and for compound characteristics of clarithromycin, midazolam, and digoxin. Published concentration-time profiles were used for model development (training dataset), and published and unpublished individual profiles were used for model evaluation (evaluation dataset). The developed single-compound PBPK models were linked for DDI predictions. The full clarithromycin DDI model successfully predicted the metabolic (midazolam) and transporter (digoxin) DDI, the acceptance criterion (0.5 ≤ AUCratio,predicted/AUCratio,observed≤ 2) was met by all predictions. During co-treatment with 250 or 500 mg clarithromycin (bid), the midazolam and digoxin doses should be reduced by 74 to 88% and by 21 to 22%, respectively, to ensure constant midazolam and digoxin exposures (AUC). With these models, we provide highly mechanistic tools to help researchers understand and characterize the DDI potential of new molecular entities and inform the design of DDI studies with potential CYP3A4 and P-gp substrates.
Department of Pharmacy, Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany.
Daniel
D
Moj
Department of Pharmacy, Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany.
Nina
N
Hanke
Department of Pharmacy, Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany.
Hannah
H
Britz
Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
Sebastian
S
Frechen
Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
Tobias
T
Kanacher
Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
Thomas
T
Wendl
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Walter Emil
WE
Haefeli
Department of Pharmacy, Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany. Thorsten.Lehr@mx.uni-saarland.de.
Thorsten
T
Lehr
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D007275:Injections, Intravenous; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D004077:Digoxin; D051544:Cytochrome P-450 CYP3A; D017291:Clarithromycin; D008874:Midazolam
PBPK; clarithromycin; digoxin; dose; drug interaction; midazolam