IngentaConnect Pharmacokinetic model and simulations of dose conversion from imm...

Abstract:

Objective: Extended-release tramadol (tramadol ER) is a once-daily formulation of tramadol approved in the United States for moderate to moderately severe chronic pain in adults. This modeling and simulation analysis was conducted to support dosing recommendations for switching patients receiving immediate-release tramadol (tramadol IR) to tramadol ER.

Research design and methods: Monte Carlo simulations based on steady-state data from three Phase 1 studies predicted minimum plasma concentration (C_min), maximum plasma concentration (C_max), and area under the plasma-concentration-versus-time curve (AUC).

Main outcome measures: Pharmacokinetic parameters were compared between 100-mg daily increments of tramadol ER every 24 h (Q24H) and corresponding 25-mg increments of tramadol IR every 6 h (Q6H), such as tramadol ER 200 mg Q24H versus tramadol IR 200, 225, 250, and 275 mg daily.

Results: Tramadol ER and IR were predicted to provide similar exposure (AUC) at a total daily dose of 100, 200, or 300 mg. Estimated exposure was comparable between tramadol IR 125-, 225-, and 325-mg and tramadol ER 100-, 200-, and 300-mg, respectively. Estimated exposure was 30-41% lower with tramadol ER 100 mg versus tramadol IR 150 and 175 mg daily, 15-26% lower with tramadol ER 200 mg versus tramadol IR 250 and 275 mg daily, and 8-19% lower with tramadol ER 300 mg versus tramadol IR 350 and 375 mg daily.

Conclusions: This pharmacokinetic analysis supports switching patients from a total daily dose of tramadol IR 200 or 300 mg directly to tramadol ER 200 and 300 mg once daily, respectively. Patients who take other doses of tramadol IR may switch to the next lower 100-mg increment of tramadol ER (e.g., from tramadol IR 225, 250, or 275 mg daily in divided doses to tramadol ER 200 mg once daily). Confirmation of these findings would require clinical studies comparing the systemic exposure of tramadol upon switching from the IR to the ER formulation.

Keywords: CONVERSION; DOSING TITRATION; EXTENDED-RELEASE; MONTE CARLO SIMULATION; PHARMACOKINETICS; TRAMADOL; TRANSITION; SWITCH

Document Type: Research article

DOI: 10.1185/030079906X162773

Affiliations: 1: Global Clinical Pharmacokinetics, Johnson & Johnson PRD, Raritan, NJ, USA 2: Medical Communications, Ortho-McNeil Janssen Scientific Affairs, LLC, Raritan, NJ, USA 3: Medical Affairs, PriCara, Unit of Ortho-McNeil, Inc., Raritan, NJ, USA

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Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol