TABLE 2

Mean intravenous and oral plasma clearance data, number of datasets, blood/plasma ratios, fraction unbound in plasma, and the observed and predicted intrinsic clearance values for 25 drugs investigated

Values in parentheses represent the 95% credible intervals for intravenous and oral plasma clearance for drugs for which more than one clinical study were available and 95% confidence intervals for the predicted CLint,h. References for all clinical studies are available at http://www.pharmacy.manchester.ac.uk/capkr/.

SubstrateIn Vivo ParametersCLint,ha
fupRbIntravenous Plasma ClearanceanOral Plasma ClearanceanIntravenousOralPredictedb
ml/min/kgml/min/kgml/min/kg
Alfentanil0.0860.634.19 (3.93, 4.46)411.4 (10.7, 12.2)471.873.9116 (55, 176)
Alprazolamc0.290.850.76 (0.71, 0.82)20.99 (0.90, 1.10)142.763.227.3
Atorvastatin0.020.558.931226 (211, 241)72,0702,71050.8 (26.0, 75.5)
Buspirone0.050.8128.311,170 (797, 1670)143,0204,920229 (178, 281)
Cisapride0.021.0d7.85 (7.08, 8.69)4216256 (186, 325)
Cyclosporine0.0681.363.99e (3.50, 4.59)712.3e,f (9.92, 14.9)811097g66.4 (30.6, 102)
Cyclosporine0.0681.363.99e (3.50, 4.59)725.4e,h (20.4, 31.0)7110201g66.4 (30.6, 102)
Felodipine0.0040.7011.9 (11.4, 12.4)4110 (88, 137)1117,02012,3001,700 (1,080, 2,330)
Indinavir0.360.84i18.4114.2 (13.1, 15.3)644030.4j498 (342, 653)
Lovastatin0.0430.57k329 (293, 368)55354,100 (2,340, 5,852)
Methadone0.210.751.66 (1.49, 1.85)52.13 (1.94, 2.34)67.487.0319.1 (13.6, 24.7)
Midazolam0.0310.556.16 (5.64, 6.72)3024.2 (20.5, 28.5)14440402367 (209, 525)
Nifedipine0.0440.677.55 (7.00, 8.14)315.6 (12.0, 17.5)14378245255 (212, 298)
Nisoldipine0.0031.0l14.4 (13.2, 15.6)4319 (280, 361)515,90011,7005,990 (3,630, 8,350)
Quinidinec0.260.873.86 (3.42, 4.35)25.64 (5.18, 6.13)311.615.07.4
Repaglinide0.0150.607.76113.7 (12.8, 14.8)211,380815110 (77.3, 142)
Rifabutin0.290.603.46116.2 (12.8, 20.5)816.611.568.1 (42.4, 93.7)
Saquinavir0.0280.7412.9 (10.3, 16.0)23,44012,9206,640g6,390 (4,410, 8,360)
Sildenafil0.040.648.9719.42 (8.72, 10.2)4694127139 (113, 166)
Simvastatin0.060.57i387 (317, 469)189036,080 (4,730, 7420)
Tacrolimus0.13350.64e (0.57, 0.73)44.93e (4.09, 5.83)8179186892 (313, 1,470)
Terfenadine0.031.01,260116,8002,940 (2,290, 3,600)
Trazodone0.071.0l2.14 (1.94, 2.34)32.27 (2.18, 2.37)834.126.954.9 (41.2, 68.6)
Triazolamc0.100.622.94 (2.77, 3.13)76.36 (5.92, 6.83)938.247.243.7
Verapamil0.0930.8911.7 (11.0, 12.5)643.3 (39.1, 47.8)6347303283 (165, 401)
Zolpidem0.080.764.25 (3.96, 4.55)25.14 (4.33, 6.06)1171.850.814.1 (8.54, 19.6)
  • a Intravenous and oral clearance data represent systemic plasma clearances. Observed CLint,h values after intravenous and oral administration were calculated using eqs. 5 and 6, respectively, after plasma clearances were corrected for renal excretion and blood/plasma ratio (CLh = (CLp − CLrenal)/Rb).

  • b CLint,h predictions based on the mean in vitro clearance data from three HLM pools.

  • c CLuint data were supplemented from Galetin and Houston (2006) for alprazolam (8.46 and 0.515 μl/min/mg in HLM and HIM, respectively), quinidine (6.60 and 2.13 μl/min/mg in HLM and HIM, respectively), and triazolam (51.2 and 4.73 μl/min/mg in HLM and HIM, respectively).

  • d —, data not available or not applicable.

  • e Blood clearance data.

  • f Oral clearance of cyclosporine (Neoral).

  • g Fraction absorbed: 0.9 and 0.3 for cyclosporine and saquinavir, respectively; otherwise complete absorption was assumed.

  • h Oral clearance of cyclosporine (Sandimmune).

  • i Provided by Pfizer, Global Research and Development.

  • j Evidence for saturation in vivo (Yeh et al., 1999).

  • k Assumed to be the same as for simvastatin.

  • l Assumed to be 1.