Physiologically based pharmacokinetic models of 2',3'-dideoxyinosine.

Abstract

PURPOSE:

The goal of this study was to develop physiologically based pharmacokinetic (PBPK) models for 2',3'-dideoxyinosine (ddI) in rats when the drug was administered alone (ddI model) and with pentamidine (ddI + pentamidine model), and to use these models to evaluate the effect of our previously reported pentamidine-ddI interaction on tissue ddI exposure in humans.

METHODS:

The PBPK models consisted of pharmacologically relevant tissues (blood, brain, gut, spleen, pancreas, liver, kidney, lymph nodes, muscle) and used the assumptions of perfusion-rate limited tissue distribution and linear tissue binding of ddI. The required physiologic model parameters were obtained from the literature, whereas the pharmacokinetic parameters and the tissue-to-plasma partition coefficients were calculated using plasma and tissue data.

RESULTS:

The ddI model in rats yielded model-predicted concentration-time profiles that were in close agreement with the experimentally determined profiles after an intravenous ddI dose (5% deviation in plasma and 20% deviation in tissues). The ddI + pentamidine model incorporated the pentamidine-induced increases of ddI partition in pancreas and muscle. The two PBPK models were scaled-up to humans using human physiologic and pharmacokinetic parameters. A comparison of the model-predicted plasma concentration-time profiles with the observed profiles in AIDS patients who often received ddI with pentamidine showed that the ddI model underestimated the terminal half-life (t1/2, beta) by 39% whereas the ddI + pentamidine model yielded identical t1/2, beta and area-under-the-curve as the observed values (< 1% deviation). Simulations of ddI concentration-time profiles in human tissues using the two models showed that pancreas and lymph nodes received about 2- to 30-fold higher ddI concentration than spleen and brain, and that coadministration of pentamidine increased the AUC of ddI in the pancreas by 20%.

CONCLUSIONS:

Data of the present study indicate that the plasma ddI concentration-time profile in patients were better described by the ddI + pentamidine model than by the ddI model, suggesting that the pentamidine-induced changes in tissue distribution of ddI observed in rats may also occur in humans.

• Authors: H J Kang, M G Wientjes, J L Au
• Journal: Pharmaceutical research (Pharm Res) Vol. 14 Issue 3 Pg. 337-44 (Mar 1997) ISSN: 0724-8741 [Print] United States
• PMID: 9098877 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Pentamidine
• Didanosine

Topics

• Animals
• Brain (metabolism)
• Didanosine (pharmacokinetics)
• Female
• Humans
• Intestinal Mucosa (metabolism)
• Kidney (metabolism)
• Liver (metabolism)
• Lymph Nodes (metabolism)
• Models, Biological
• Muscles (metabolism)
• Pancreas (metabolism)
• Pentamidine (pharmacology)
• Rats
• Rats, Inbred F344
• Spleen (metabolism)