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.
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 AIDSpatients 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: G M Shaw; M E Harper; B H Hahn; L G Epstein; D C Gajdusek; R W Price; B A Navia; C K Petito; C J O'Hara; J E Groopman Journal: Science Date: 1985-01-11 Impact factor: 47.728
Authors: T H Grasela; C A Walawander; M Beltangady; C A Knupp; R R Martin; L M Dunkle; R H Barbhaiya; K A Pittman; R Dolin; F T Valentine Journal: J Infect Dis Date: 1994-06 Impact factor: 5.226
Authors: C A Knupp; W C Shyu; R Dolin; F T Valentine; C McLaren; R R Martin; K A Pittman; R H Barbhaiya Journal: Clin Pharmacol Ther Date: 1991-05 Impact factor: 6.875