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Clarithromycin, Midazolam, and Digoxin: Application of PBPK Modeling to Gain New Insights into Drug-Drug Interactions and Co-medication Regimens.
- Source :
-
The AAPS journal [AAPS J] 2017 Jan; Vol. 19 (1), pp. 298-312. Date of Electronic Publication: 2016 Nov 07. - Publication Year :
- 2017
-
Abstract
- 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 Published concentration-time profiles were used for model development (training dataset), and published and unpublished individual profiles were used for model evaluation (evaluation dataset).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 ≤ AUC <subscript>ratio,predicted</subscript> /AUC <subscript>ratio,observed</subscript> ≤ 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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
Administration, Oral
Clarithromycin administration & dosage
Cytochrome P-450 CYP3A metabolism
Digoxin administration & dosage
Dose-Response Relationship, Drug
Drug Interactions
Drug Therapy, Combination
Humans
Injections, Intravenous
Midazolam administration & dosage
Organic Anion Transporters antagonists & inhibitors
Substrate Specificity
Clarithromycin pharmacokinetics
Digoxin pharmacokinetics
Midazolam pharmacokinetics
Models, Biological
Subjects
Details
- Language :
- English
- ISSN :
- 1550-7416
- Volume :
- 19
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The AAPS journal
- Publication Type :
- Academic Journal
- Accession number :
- 27822600
- Full Text :
- https://doi.org/10.1208/s12248-016-0009-9