Muhammad Waqas Sadiq(1), Emma Boström(2), Ron Keizer(1), Sven Björkman(1), Margareta Hammarlund-Udenaes(1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-75124 Uppsala, Sweden. ; (2) AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden.
Objectives: This study aimed to characterize the BBB transport and pharmacokinetic and pharmacodynamic (PKPD) relationship of oxymorphone in rats using population modeling and to quantify its contribution to the analgesia as a metabolite of oxycodone.
Methods: Transport of oxymorphone across the BBB was studied with microdialysis (MD) in male Sprague-Dawley rats. Samples from microdialysis blood and brain probes were analyzed with LC-MS/MS. The analgesic effect of oxymorphone was studied in rats by measuring the tail flick latency. The study consisted of a PKPD experiment with combined microdialysis and antinociceptive effect measurements (Group 1, n = 8) as well as a separate antinociceptive effect experiment (Group 2, n = 9). In Group 2, the dose of oxymorphone administered was 10 times lower than in Group 1. Non-linear mixed effects modeling was used to analyze the PK data from plasma, MD brain and blood samples and the PD data of tail flick latency, using NONMEM, and Pirana as the modeling environment. Censored observations in the PD data from Group 1 were treated with the ‘M3 method' [1] adapted to handle data above the upper limit of quantification (15 seconds) in the PKPD model in order to fully utilize the PD information. Model selection and evaluation was performed using likelihood ratio tests and visual predictive checks.
Results: Oxymorphone had higher unbound concentration in brain than in blood with a ratio of unbound drug in brain interstitial fluid to unbound in blood (Kp,uu) of 1.87 (10%), indicating the presence of active uptake transport of oxymorphone [2]. The uptake clearance (CLin) into the brain for oxymorphone was 72.4 µl/min/g-brain and the efflux clearance (Clout) was 38.7 µl/min/g-brain. The integrated PK model with an Emax effect model best described the oxymorphone BBB transport and PKPD relationship. All parameters could be estimated with high precision (RSE<15%), except for EC50 and Emax. The EC50 (unbound brain concentrations) of oxymorphone was estimated 62.6 (82%) ng/ml, corresponding to an unbound plasma EC50 of 33.5 ng/ml.
Conclusions: Oxymorphone has active uptake transport at the BBB, thus low distribution to the CNS is not the explanation for its probable lack of contribution to the effects of oxycodone. However the amount of oxymorphone produced by metabolism is not enough to contribute significantly in producing analgesia after oxycodone administration.
References:
(1) Beal, S.L., Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn, 2001. 28(5): p. 481-504.
(2) Hammarlund-Udenaes, M., et al., On the rate and extent of drug delivery to the brain. Pharm Res, 2008. 25(8): p. 1737-50.
Reference: PAGE 21 (2012) Abstr 2429 [www.page-meeting.org/?abstract=2429]
Poster: Other Modelling Applications