PII-118 - EFAVIRENZ ALTERS THE DISPOSITION AND PHARMACODYNAMICS OF TIZANIDINE IN HEALTHY VOLUNTEERS

Y. Wu¹, A. Rashidian¹, W. Osei^2,3, J. Lu¹, A. Colwell¹, Z. Desta⁴; ¹Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States, ²Department of Pharmacy Practice, School of Pharmacy, Purdue University, Indianapolis, IN, USA, ³Purdue University, West Lafayette, IN, USA, ⁴Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis,IN, US.

Background: Efavirenz, a key HIV medication may inhibit CYP1A2. Tizanidine, a muscle relaxant, is primarily metabolized by CYP1A2 and serves as a sensitive probe for this enzyme. Tizanidine exhibits large intersubject variability in its exposure, and concentration-dependent adverse effects (e.g., hypotension) often occur. Thus, we examined whether efavirenz alters the disposition and effects of tizanidine.

Methods: In this ongoing open-label, fixed-sequence, three-phase trial, healthy non-smoking volunteers aged 18–65 received a 4 mg oral dose of tizanidine (Sun Pharma, Princeton, NJ) on two occasions: at baseline (control) and again alongside the final dose of efavirenz after a 16-day pre-treatment with 600 mg/day efavirenz (SUSTIVA®, Camber, Piscataway, NJ). Serial plasma samples and pharmacodynamics (PD) data, including blood pressure and heart rate, were collected at before and after tizanidine dosing. Plasma concentrations of tizanidine and its metabolites were quantified using a new UHPLC-MS/MS method. Pharmacokinetic (PK) parameters were analyzed via noncompartmental method. Paired t-tests were used to compare data between the control and after efavirenz treatment.

Results: PK data from 9 subjects and PD data from 12 subjects who completed the entire study are presented here. The geometric mean with 95% confidence interval (CI) of Cmax increased from 2.5 ng/mL (CI: 1.1, 6.1) in the control to 4.9 ng/mL (CI: 2.6, 9.4) after efavirenz treatment (p=0.014). Similarly, the AUC0-∞ nearly doubled, with 8.1 ng*h/mL (CI: 3.6, 18) in control versus 18 ng*h/mL (CI: 9.6, 33) after efavirenz treatment (p=0.008). The Cmax of CYP1A2-dependent metabolites were lower in the efavirenz treated group. The mean area under the effects curve (AUEC0-10h) of systolic blood pressure was significantly decreased (p = 0.009) to 1093 mmHg*h (95% CI: 1019, 1168) in the efavirenz treated group, compared to 1155 mmHg*h (CI: 1075, 1235) in the control group. No significant changes were observed in other PD biomarkers.

Conclusion: This study is the first to demonstrate that efavirenz increases tizanidine exposure through the inhibition of CYP1A2 and this interaction is associated with decreased systolic blood pressure. Recruitment is still ongoing, and more data will be available at the time of the presentation.