Table 2.
Reported population PK parameters for immune checkpoint inhibitorsa
| Generic name (isotype) | No. of patients | Dose range (mg/kg ) | t½ (days) | PopPK model | CL (L/day) | Vc (L) | Vp (L) | Q (L/day) | Vmax (mg/day)/Km (mg/L) | IIV (CV%) | Covariatesb,c [% of IIV attributable to covariates conjointly] | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ipilimumab (IgG1) | 499 | 0.3–10 | 15 | 2-comp, LE | 0.36 | 4.15 | 3.11 | 0.9864 |
CL: 35.4% Vc: 14.9% |
(BW(0.642) POWER,80KG + LDH(1.13) POWER,206IU/L) ~ CL[24%] (BW(0.708) POWER,80KG) ~ Vc [52%] |
[13] | |
| Atezolizumab (IgG1) | 906 | 1–20 | 27 | 2-comp, LE | 0.20 | 3.28 | 3.63 | 0.546 |
CL: 29% Vc: 18% Vp: 34% |
(ALBU(− 1.12)40G/L + ADA(0.159)PRESENCE + BW(0.808)77KG +TB(0.125)) 63MM ~ CL[15%] (ALBU(− 0.350)40g/L + BW(0.559) 77KG + SEX(− 0.129)) Female ~ Vc[5.6%] (SEX(− 0.272))Female ~ Vp (BW)77KG ~ AUCss |
[18] | |
| Avelumab (IgG1) | 1629 | 1–20 | 6.1 | 2-comp, LE | 0.59 | 2.83 | 1.17 |
CL: 25.2% Vc: 18.3% Vp: 1.05% |
(ALBU(− 0.5)BASELINE + BW(0.358)BASELNE + CANC(− 2.24)MCC + DOSE(0.26)3MG/L + SEX(0.199)MALE + TB(0.095))BASELINE ~ CL (ACE(− 0.56)YES + CANC(− 0.864)MCC /CANC(− 0.692)NSCLC ~ Q (BW(0.367) BASELINE + SEX(0.203))MALE ~ Vc (ACE(− 0.233)YES + CANC(0.723)HNC/CANC(8.58)MCC + eGFR(− 0.507) + ADA(− 0.667))PRESENCE ~ Vp |
[22] | ||
| Durvalumab (IgG1) | 1324 | 0.1–20 | 21 | 2-comp, LE + NLE | 0.232 | 3.51 | 3.45 | 0.476 | 0.824/0.344 |
CL: 27.2% Vc: 22.1% |
(ADA(0.234)PRESENCE + ALBU(− 0.0350)POWER,38G/L + BW(0.389)POWER,69KG + CANC(0.00178)UC + CLcr(0.00149)LINEAR,87ML/MIN + ECOG(− 0.0630)SCORE=0 + LDH(0.0915)POWER,240IU/L + SEX(− 0.143)FEMALE +SPDL1(0.0844)POWER,124PG/ML) ~ CL[15%] (BW(0.406)POWER,69KG + SEX(− 0.205)FEMALE) ~ Vc; |
[29] |
| Nivolumab (IgG4) | 1895 | 0.1–20 | 25 | 2-comp, LE | 0.23 | 3.63 | 2.78 | 0.770 |
CL: 35% Vc: 35.1% |
(BW(0.566) POWER,80KG + eGFR(0.186)POWER,90ML/MIN + PS(0.172),PS=0 + RACE(− 0.125)ASIAN + SEX(18%) MALE) ~ CL[30%] (BW(0.597) POWER,80KG + SEX(0.152) MALE) ~ Vc [21%] |
[32] | |
| Pembrolizumab (IgG4) | 1223 | 1–10 | 27.3 | 2-comp, LE | 0.22 | 3.48 | 4.06 | 0.795 |
CL: 38% Vc: 21% |
(ALBU(− 0.907)POWER,39.6G/L + ECOG-PS(− 0.0739)SCORE=1 + eGFR(0.135)POWER,88ML/MIN + IPIP(0.140)PRIORTREATMENT + SEX(− 0.152)FEMALE + TB(0.0872)NSCLC) ~ CL[32%] (ALBU(− 0.208) POWER,39.6G/L + IPIP(0.0736)YES + SEX(− 0.134) FEMALE) ~ Vc |
[41] | |
| Not given | 0.02–10 | 14–22 | 2-comp, LE + NLE | 0.168 | 2.88 | 2.85 | 0.384 | 0.114/0.0784 | – | [39] | ||
| 2841 | 1–10 | 2-comp, LE, TV | 0.249 | 3.47 | 2.96 | 0.889 |
CL: 30.7% Vc: 19.6% |
(ALBU(− 0.9)POWER,77KG + BR(− 0.0521)POWER,8.88μmol/L + CANC(0.0774) ADDITIVE, MELANOMA=1,NSCLC=2 + eGFR(0.122) POWER,91mL/min + ECOG(0.065)ADDITIVE,BASELINE + SEX(− 0.158) ADDITIVE,FEMALE=1,MALE=2) + TB(0.102)POWER,BASELINE) ~ CL (ALBU(− 0.219) POWER,77KG + SEX(− 0.128)ADDITIVE,FEMALE=1,MALE=2) ~ Vc |
[40] |
ACE acetaminophen premedication (yes or no), ADA post-baseline antidrug antibody status (presence or absence), AGE age (years), ALBU serum albumin concentration (g/L), AUCss area under the concentration–time curve at steady state, BR bilirubin (μmol/L), BW body weight (kg), CANC cancer type, CL apparent total clearance, CLcr creatinine clearance (mL/min), comp compartment, CV% percentage coefficient of variation, ECOG PS Eastern Cooperative Oncology Group performance status (0–5), eGFR estimated glomerular filtration rate (mL/min), Ig immunoglobulin, IIV interindividual variability, IPIP prior treatment with ipilimumab, Km Michaelis–Menten constant, LDH lactate dehydrogenase (IU/L), LE linear elimination, NLE nonlinear elimination, NSCLC nonsmall cell lung cancer, PK pharmacokinetics, popPK population pharmacokinetic, PS baseline performance status, Q intercompartmental clearance, RACE race or ethnicity, SEX sex (male or female), SPDL1 soluble programmed death-ligand 1, t½ half-life,TB tumor burden (mm), TV time variant, Vc central volume of distribution, Vp peripheral volume of distribution, Vmax maximum rate of NLE
aOnly parameter estimates from peer-reviewed journal publications (or drug labels, in cases where no publications were available) are reported here as most conference abstracts do not provide sufficient information on parameter estimation or model structure
bNot all covariates are clinically significant when they are statistically significant
cCovariates are represented as COV(estimation)EQUATION,BASELINE, where COV is the covariate, estimation is the estimated value for the covariate, equation represents the equation structure used for the covariate, and baseline represents the value to which the covariate becomes scaled (i.e. 80 kg) or the baseline covariate to which the equation applies (i.e. females, baseline tumor size). In case such information was not provided, the missing part was left blank