. 2022 Oct 17;11(11):1458–1471. doi: 10.1002/psp4.12855

TABLE 1.

Cemiplimab PK parameters after modeling with the analysis dataset or bootstrap datasets for the final PopPK model

Parameter	Final PopPK model				Bootstrap datasets (N = 474) ^a
Parameter	Estimate	ASE	%RSE	95% CI ^b	Mean	Median	95% CI ^b
Fixed effects
TVCL0, L/day	0.254	0.00395	1.56	0.246, 0.262	0.254	0.254	0.241, 0.269
TVQ, L/day	0.652	0.0238	3.65	0.606, 0.699	0.650	0.651	0.581, 0.728
TVV₁, L	3.35	0.0422	1.26	3.27, 3.44	3.35	3.35	3.27, 3.44
TVV₂, L	2.52	0.0419	1.66	2.44, 2.60	2.52	2.51	2.29, 2.81
TVE_max	−0.174	0.00838	4.82	−0.190, −0.157	−0.181	−0.180	−0.232, −0.136
TVT₅₀, days	73.7	5.57	7.56	62.8, 84.7	90.8	74.4	46.2, 245
HILL	2.50 ^c	—	—	—
CL_WGTBL	0.539	0.0496	9.19	0.442, 0.637	0.539	0.539	0.443, 0.639
V_ssWGTBL	0.499	0.0501	10.0	0.401, 0.597	0.499	0.501	0.412, 0.569
CL_SEX	−0.137	0.0180	13.2	−0.172, −0.101	−0.133	−0.134	−0.167, −0.0925
V_1SEX	−0.0801	0.0186	23.3	−0.117, −0.0435	−0.0798	−0.0794	−0.115, −0.0471
V_1ALBBL	−0.217	0.0617	28.4	−0.338, −0.0961	−0.221	−0.225	−0.361, −0.0870
CL_ALB	−1.11	0.0269	2.42	−1.16, −1.06	−1.12	−1.11	−1.24, −0.984
CL_ALTBL	−0.0729	0.0162	22.2	−0.105, −0.0411	−0.0724	−0.0720	−0.108, −0.0370
CL_CSCC	−0.216	0.0206	9.55	−0.256, −0.176	−0.219	−0.219	−0.257, −0.181
CL_BCC	−0.211	0.0258	12.2	−0.261, −0.160	−0.209	−0.209	−0.261, −0.158
E_maxBCC	−0.872	0.110	12.6	−1.09, −0.657	−0.841	−0.870	−1.00, −0.517
T_50OTHER	−0.491	0.0595	12.1	−0.608, −0.374	−0.537	−0.518	−0.987, −0.169
Residual variability
RE	0.241 ^d	0.000366	0.15	0.240, 0.242 ^d	0.241 ^d	0.240 ^d	0.227, 0.258 ^d
IIV
ETA1 – CL_Q	0.0892	0.00362	4.05	0.0822, 0.0963	0.0886	0.0884	0.0759, 0.101
ETA2 – V₁_V₂	0.0709	0.00144	2.03	0.0681, 0.0737	0.0692	0.0674	0.0459, 0.105
OFV	−27,190.388

Note: The η‐shrinkage values were 7.8% for CL_Q and 8.5% for V₁_V₂.

Time‐dependent CL was modeled using a sigmoid E_max relationship: $TVCL = TVCL 0 \cdot \exp (\frac{Emax \cdot T^{γ}}{T 50^{γ} + T^{γ}})$ .

Abbreviations: ASE, asymptotic standard error; BCC, basal cell carcinoma; CI, confidence interval; CL, clearance; CL_ALB, covariate impact of time‐varying albumin on CL; CL_ALTBL, covariate impact of baseline alanine aminotransferase on CL; CL_BCC, covariate impact of BCC tumor type on CL; CL_CSCC, covariate impact of CSCC tumor type on CL; CL_SEX, covariate impact of female sex on CL; CL_WGTBL, covariate impact of baseline body weight on CL_Q; CSCC, cutaneous squamous cell carcinoma; E_max, maximum effect in sigmoid model; E_maxBCC, covariate impact of BCC tumor type on E_max; η, interindividual random effects; HILL, hill exponent (γ) in the sigmoid E_max function describing the change in CL with time; IIV, interindividual variability; OFV, objective function value; PK, pharmacokinetics; PopPK, population PK; Q, intercompartmental clearance between the central and peripheral compartments; RE, residual error; RSE, relative standard error; SCC, squamous cell carcinoma; T₅₀, time to reach 50% of the maximum change in CL; T_50OTHER, covariate impact of other tumor type on T₅₀; TVCL0, typical value of clearance at baseline; TVE_max, typical value of maximum change in CL with time; TVQ, typical value of inter‐compartmental clearance; TVT₅₀, typical value of time to reach 50% of the maximum change in CL; TVV₁, typical value of central volume of distribution; TVV₂, typical value of peripheral volume of distribution; V₁, distribution volume of central compartment; V₂, distribution volume of peripheral compartment; V_1ALBBL, covariate impact of baseline albumin on V₁; V_1SEX, covariate impact of female sex on V₁; V_ssWGTBL, covariate impact of baseline body weight on V₁_V₂.

^{^a}

Results are summarized for 474 of 500 bootstrap runs that converged successfully and had condition number <1000.

^{^b}

The 2.5th and 97.5th percentiles of parameter distributions are reported as the 95% CI.

^{^c}

The HILL parameter in the sigmoid E_max function for time‐varying CL was fixed at 2.50.

^{^d}

Residual error is represented as a positive value by calculating the square root of (estimate)².