Table 1.

Dasabuvir PBPK model verification and predictions, with predicted vs. observed DDI for C_max and AUC ratios

Coadministered drug	Dasabuvir
	Cmax ratio			AUC ratio
	Observed6	Predictedc	Rpred/obs	Observed6	Predictedc	Rpred/obs
Ketoconazolea	1.5	1.4 (1.2–2.2)	0.9	1.6	1.7 (1.2–3.0)	1.1
Ritonavir SSb	0.4	0.7 (0.3 –1.4)	1.6	0.5	0.5 (0.2 –2.0)	1.0
Gemfibrozilb	2.0	2.6 (1.4–7.6)	1.3	11	10 (2.7–27)	0.9
Trimethoprimb	1.2	1.6 (1.2–2.2)	1.3	1.3	2.0 (1.0–4.5)	1.5

Study designs in PBPK model simulations were matched with each clinical study design. For simulations of the gemfibrozil trial with dasabuvir, the previously validated gemfibrozil PBPK model in Simcyp v14.1 was used, where gemfibrozil 1‐O‐β‐glucuronide metabolite was considered as a CYP2C8 mechanism‐based inhibitor.12 SS, steady state; R_pred/obs, Predicted C_max or AUC ratio/Observed C_max or AUC ratio.

^aRitonavir not present in this trial simulation to match clinical study design. Dasabuvir 250 mg b.i.d. with ketoconazole 400 mg single dose on day 11.

^bRitonavir dosage was 100 mg q.d. with dasabuvir 400 mg b.i.d. to match clinical study design.

Gemfibrozil dosage was 600 mg b.i.d. with dasabuvir 400 mg single dose on day 3 to match clinical study design. Gemfibrozil 1‐O‐glucuronide CYP2C8 K_I was optimized from initial value in Simcyp (19 μM) to 4 μM, a 2‐fold lower value than the reported K_I of 7.9 μM.13

Trimethoprim dosage was 160 mg b.i.d. with dasabuvir 250 mg single dose on day 3 to match clinical study design.

^cPredictions are shown as geometric mean and the range (minimum and maximum) is in parentheses.

All simulation results are based on 10 virtual trials of 10 subjects each to account for population variability.