Pharmacokinetics and Tolerability of Tapentadol Immediate Release (IR) in Subjects With Hepatic or Renal Impairment (2009)

Purpose: Tapentadol is a centrally acting analgesic that is cleared mainly via phase 2 conjugation (primarily to its O-glucuronide); metabolites are excreted by the kidneys. Here we report results from 2 studies evaluating the pharmacokinetics (PK) and tolerability of tapentadol IR in subjects with hepatic or renal impairment. Methods: For the hepatic and renal impairment studies, subjects were classified into hepatic impairment groups (normal, mild, moderate) using the Child-Pugh classification or renal impairment groups (normal [renal creatine clearance (CLCR), ≥80mL/min], mild [CLCR, 50 to <80mL/min], moderate [CLCR, 30 to <50 mL/min], or severe [CLCR, <30mL/min]) estimated by the Cockcroft-Gault formula and received a single, oral, 80-mg dose of tapentadol IR. Blood and urine samples were taken during the 48 h after study drug administration for PK analyses; tapentadol and tapentadol-O-glucuronide concentrations were determined by LC/MS/MS. Results: Compared with PK values for subjects (n=10) with normal hepatic function, in subjects with mild (n=10) and moderate (n=10) hepatic impairment, respectively, Cmax for tapentadol increased 1.4- and 2.5-fold, AUClast increased 1.7- and 4.2-fold, and t1/2 increased 1.2- and 1.4-fold; for tapentadol-O-glucuronide, Cmax remained similar and decreased 2-fold, AUClast remained similar for both groups, and t1/2 increased 1.2- and 1.6-fold, respectively. Subjects with increasing renal impairment had increased exposure to tapentadol-O-glucuronide, but tapentadol exposure was similar. In the mild (n=10), moderate (n=10), and severe (n=10) renal impairment groups, respectively, AUClast (tapentadol-O-glucuronide) was 1.5-, 2.6-, and 5.1-fold higher than in the normal renal function group (n=9), while the t1/2 for tapentadol-O-glucuronide increased from 4.3 ±0.2h (normal renal function group) to 5.1 ±1.6h, 6.7±2.0h, and 14.2±8.0h. The most common adverse events in both studies were dizziness, fatigue, nausea, feeling abnormal, and headache. Conclusion: In these 2 studies, the tolerability profile of tapentadol IR was consistent with previous observations in healthy subjects in other single-dose studies. Subjects with hepatic impairment had higher exposure to and higher serum levels of tapentadol than subjects with no impairment. Subjects with increasing renal impairment had increased exposure to and higher serum levels of tapentadol-O-glucuronide. Results of these studies indicate that tapentadol IR dose adjustments should be considered in patients with moderate hepatic impairment; no dose adjustments are required for patients with mild hepatic or mild or moderate renal impairment. Tapentadol is not recommended for patients with severe renal or hepatic impairment. Disclosure: Dr Smit - Employee: Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica, N. V.; Dr Mangold - Former employee: Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica, N. V. Dr Oh - Employee: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr Rengelshausen - Employee: Grünenthal GmbH Dr Laschewski - Employee: Grünenthal GmbH Dr Flügel - Employee: Grünenthal GmbH Dr Upmalis - Employee: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr Häufel - Employee: Grünenthal GmbH. This research was supported by an industry grant from Johnson & Johnson and Grünenthal GmbH provided financial support for this study.