Clinical Toxicity Associated with Increased Drug Exposure

• Indinavir (urologic complaints)

  • Dieleman et al. AIDS 1999;13:473-8.

• Ritonavir (GI, neurologic):

  • Merry et al. Br J Clin Pharmacol 1996;42:787.
  • Gatti et al. AIDS 1999;13:2083-9.
  • Youle et al. ICAAC 1999, #1290.

• Nelfinavir, Saquinavir (GI symptoms except diarrhea):

  • Reijers et al. AIDS. 2000 Jan 7;14(1):59-67.

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Indinavir:

• Anecdotal data show that high exposure to indinavir is associated with an increased risk for urological complaints (flank pain, haematuria, renal colic).

• Hypothesized that Cmax of indinavir is correlated with renal toxicity.

• Data from the BEST trial suggest that renal toxicity is more often encountered when used in a RTV/IDV 100/800 mg bid regimen as compared to IDV 800 mg tid alone, suggesting that AUC or time > certain concentration rather than Cmax might be the main determinant of renal toxicity

Ritonavir:

• High ritonavir exposure has been associated with increased risk for gastrointestinal and neurological complaints. These associations have been reported for AUC, Cmax and Cmin (all correlated).

Nelfinavir and Saquinavir:

• High drug exposure has been associated with increased risk for gastrointestinal complaints such as abdominal pain, distension, and nausea to both nelfinavir and saquinavir. NB: in this study, the incidence/severity of diarrhea was not correlated to drug exposure.