Universität zu Köln

Kretschmar, Melanie, Suleiman, Ahmed Abbas, Krause, Petra, Albrecht, Uwe, Stein, Raimund, Rubenwolf, Peter, Fuhr, Uwe and Taubert, Max (2021). A Population Pharmacokinetic Model of (R)- and (S-) Oxybutynin and Its Active Metabolites After Oral and Intravesical Administration to Healthy Volunteers. J. Clin. Pharmacol., 61 (7). S. 961 - 972. HOBOKEN: WILEY. ISSN 1552-4604

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Abstract

Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kretschmar, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Suleiman, Ahmed Abbas UNSPECIFIED UNSPECIFIED UNSPECIFIED Krause, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Albrecht, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Stein, Raimund UNSPECIFIED UNSPECIFIED UNSPECIFIED Rubenwolf, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, Max UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-585599
DOI:	10.1002/jcph.1809
Journal or Publication Title:	J. Clin. Pharmacol.
Volume:	61
Number:	7
Page Range:	S. 961 - 972
Date:	2021
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1552-4604
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CONTROLLED-RELEASE OXYBUTYNIN; NEUROGENIC BLADDER; DRUG ABSORPTION; IN-VITRO; RELATIVE BIOAVAILABILITY; OVERACTIVE BLADDER; DESETHYLOXYBUTYNIN; FORMULATION; ENANTIOMERS; EFFICACY Multiple languages Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58559