Absorption and in vivo dissolution of hydroxycholoroquine in fed subjects assessed using deconvolution techniques.

Abstract

1. Nine healthy subjects each received three doses of 155 mg rac-hydroxychloroquine, as a tablet, an oral solution and by intravenous infusion, in a randomised cross-over design study, 30 min after a standard high fat breakfast. 2. Four methods of deconvolution were used to assess the absolute bioavailability of the tablet and oral solution doses. These were the delta function method, the staircase approximation method, and two least squares methods using a single first-order input and a sequential first-order input. The mean (+/- s.d.) fraction absorbed estimated by the four methods was 0.64 +/- 0.14 after the tablet and 0.87 +/- 0.30 after the oral solution. Wide intersubject variability was observed (0.50-0.91 for the tablet; 0.30-1.37 for the solution). 3. The mean (+/- s.d.) absorption half-life was 3.7 +/- 2.0 h for the tablet and 3.3 +/- 1.6 h for the solution, suggesting that absorption following the tablet dose was not rate-limited by dissolution. 4. The in vivo dissolution rate, extent of release and lag-time were determined using cube-root law and first-order input functions. Dissolution was found to be rapid, after a significant lag-time, but incomplete in some subjects. 5. The rate and extent of absorption was similar to that reported previously for fasted subjects. The lag-time before absorption commenced in fed subjects (1.65 +/- 0.46 h) showed a significant three-fold increase over that reported previously in fasting subjects (0.63 +/- 0.33 h), but this difference is not likely to be of clinical significance.