. 2020 Dec 6;109(5):1314–1325. doi: 10.1002/cpt.2096

Table 2.

Parameter estimates from the final population pharmacokinetics model for released drug

Parameter	Final released‐drug model					Bootstrap analysis ^a		Sensitivity analysis with inclusion of outliers
	Estimate		Between‐patient variability			Estimate		Estimate
	Typical value	RSE ^b (%)	Magnitude (%CV)	RSE ^b (%)	Shrinkage ^c (%)	Typical value	95% CI	Typical value	RSE ^b (%)
Released‐drug clearance (CL_drug, L/h)	19.2	4.41	25.4	6.31	37.8	19.1	17.8–20.4	19.1	4.50
Released‐drug volume of distribution (V_drug, L)	Fixed 17•BSA	—	42.0	4.64	19.9	Fixed 17•BSA	—	Fixed 17•BSA	—
Release rate (Krel, 1/h)	0.0159	4.42	37.6	4.56	16.0	0.0159	0.0146–0.0172	0.0158	4.37
Fraction of Krel when cycle > 1	0.830	1.62	22.9	4.01	17.5	0.829	0.803–0.859	0.828	1.85
Cycle effect on Krel	–0.137	5.23	—	—	—	–0.137	–0.160 to −0.114	–0.139	5.40
Ritonavir on CL_drug	–0.113	13.9	—	—	—	–0.112	–0.236 to −0.0177	–0.113	15.2
Itraconazole on CL_drug	–0.103	19.0	—	—	—	–0.104	–0.159 to −0.0535	–0.103	20.9
AST on CL_drug	–0.219	14.5	—	—	—	–0.221	–0.290 to −0.150	–0.206	15.2
Total bilirubin on CL_drug	–0.207	18.4	—	—	—	–0.209	–0.294 to −0.128	–0.191	19.7
Body weight on CL_drug	0.440	18.9	—	—	—	0.448	0.299–0.576	0.480	17.6
Age on V_drug	0.562	16.8	—	—	—	0.558	0.377–0.750	0.644	15.4
FL‐DP2 formulation on V_drug	0.255	28.0	—	—	—	0.258	0.115–0.392	0.278	27.1
FL‐DP1 formulation on V_drug	–0.212	20.4	—	—	—	–0.215	–0.289 to −0.124	–0.209	21.1
Residual variability ^d
Proportional residual error SD	0.279	0.483	—	—	—	0.279	0.272–0.288	0.298	0.380
Between‐patient variability
Variance of CL_drug	0.0647	12.6	—	—	—	0.0623	0.0340–0.102	0.0705	12.1
Variance of V_drug	0.176	9.28	—	—	—	0.175	0.141–0.211	0.178	9.73
Variance of Krel	0.142	9.13	—	—	—	0.142	0.116–0.175	0.140	9.57
Variance of fraction of Krel when cycle> 1	0.0524	8.01	—	—	—	0.0525	0.0438–0.0635	0.0692	6.84

AST, aspartate aminotransferase; BSA, body surface area; CI, confidence interval; CL_drug, released drug clearance; CV, coefficient of variation; FL‐DP1, frozen liquid drug product 1; FL‐DP2, frozen liquid drug product 2; Krel, release‐rate constant; RSE, relative standard error; V_drug, released drug volume of distribution; —, not applicable.

^{^a}

200 bootstrapped data sets were used.

^{^b}

RSEs of parameter estimate are calculated as 100 × (SE/typical value); RSEs of between‐patient variability magnitude are presented on %CV scale and approximated as 100 × (SE/variance estimate)/2.

^{^c}

Shrinkage (%) is calculated as 100 × (1 − variance of post hoc/estimated variance).

^{^d}

Overall residual variability shrinkage was estimated to be 8.74%.