TABLE 2.
Summary of the model-building steps of the population pharmacokinetic analysis of VGCa
| Hypothesis | Model | θa | θb | θc | θd | θe | θf | ΔOFb | OFc |
|---|---|---|---|---|---|---|---|---|---|
| Model structure | |||||||||
| One-compartment, 1st order | ω(CL) | −4349.5 | |||||||
| Two-compartment, 1st order | ω(CL) | −37.5 | −4386.9 | ||||||
| Model variability (ω) | |||||||||
| GFRC-G on CL, variability on CL | CL = θa·GFRC-G ω(CL) | 1.41 | −200.9 | −4587.8 | |||||
| and variability on V1 | CL = θa·GFRC-G ω(CL, V1) | 1.41 | 21.6 | −20.3 | −4608.2 | ||||
| and variability on V1 and Q | CL = θa·GFRC-G ω(CL, V1, Q) | 0.83 | 8.6 | 69.3 | −4538.8 | ||||
| and variability on V1 and V2 | CL = θa·GFRC-G ω(CL, V1, V2) | 1.32 | 14.5 | −3.3 | −4611.5 | ||||
| Covariate analysis | |||||||||
| Four-variable MDRD estimated GFR | CL = θa·GFRMDRD | 1.52 | −2.9 | −4899.7 | |||||
| Extrarenal CL? | CL = θa·GFRC-G + θb | 1.35 | 0.015 | +0.8 | −4896.0 | ||||
| Does gender influence CL (GFRC-G)? | CL = θa·GFRC-G ·θbsex (sex = 0 if male, sex = 1 if female) | 1.27 | 1.23 | −10.5 | −4907.3 | ||||
| Does gender influence CL (GFRMDRD)? | CL = θa·GFRMDRD·θbsex (sex = 0 if male, sex = 1 if female) | 1.43 | 1.24 | −16.4 | −4913.2 | ||||
| Does ICAL influence CL? | CL = θa·GFRC-G·θbICAL | 1.40 | 0.79 | −16.6 | −4913.4 | ||||
| Does MMF influence CL? | CL = θa·GFRC-G·θbMMF | 1.36 | 0.99 | 0.0 | −4896.8 | ||||
| Does IOAT influence CL? | CL = θa·GFRC-G·θbIOAT | 1.37 | 0.98 | −0.3 | −4897.1 | ||||
| Does COTM influence CL? | CL = θa·GFRC-G·θbCOTM | 1.30 | 1.06 | −3.4 | −4900.2 | ||||
| Does Card influence CL? | CL = θa·GFRC-G·θbCard | 1.33 | 1.05 | −0.5 | −4897.3 | ||||
| Does graft type influence CL? | CL = θgraft·GFRC-G (K: θa, H: θb, Lu/Li: θc) | 1.50 | 0.90 | 1.31 | −34.1 | −4930.9 | |||
| Does BW influence V1? | V1 = θd·(BW/70) | 30.0 | −30.4 | −4927.2 | |||||
| Does gender influence V1? | V1 = θd·θesex (sex = 0 if male, sex = 1 if female) | 28.7 | 0.64 | −16.0 | −4912.8 | ||||
| Do BW and gender influence V1? | V1 = θd·(BW/70)·θesex (sex = 0 if male, sex = 1 if female) | 27.7 | 0.79 | −5.3 | −4932.4 | ||||
| Does HGT influence V1? | V1 = θd·(HGT/170) | 29.2 | −6.7 | −4903.5 | |||||
| Do BW and HGT influence V1? | V1 = θd·(BW/70)·(HGT/170) | 26.4 | −1.5 | −4928.6 | |||||
| Does graft type influence V1? | V1 = θgraft·(BW/70) (K: θd, H: θe, Lu/Li: θf) | 30.1 | 29.6 | 30.2 | −30.4 | −4927.2 | |||
| Simple model | CL = θa·GFRC-G | 1.35 | −4927.2 | ||||||
| V1 = θd·(BW/70) | 30.0 | ||||||||
| Interoccasion variability (IOV) on CL | CL = θa·GFRC-G | 1.39 | −62.1 | −4989.3 | |||||
| V1 = θd·(BW/70) | 23.2 | ||||||||
| Final model with IOV | CL = θgraft·GFRMDRD (K: θa, H: θb, Lu/Li: θc)·θdsex | 1.68 | 0.86 | 1.17 | 1.21 | −66.4 | −5055.7 | ||
| V1 = θe·(BW/70)·θfsex | 24.0 | 0.72 |
a
GFRC-G, GFR estimated with Cockroft-Gault formula (liters/h); ICAL (tacrolimus = 0, cyclosporine = 1); IOAT, OAT inhibitors; Card, cardiopathy; K, kidney recipients; H, heart recipients; IOV, interoccasion variability; Lu/Li, lung and liver recipients; GFRMDRD, GFR estimated with four-variable MDRD formula (liters/h); BW, body weight (in kg); HGT, height (in cm).
b
ΔOF, difference in the NONMEM objective function compared to the best previous model.
c
OF, NONMEM objective function.