Table II.
Covariate Effects of Specific Genotypes on the Pharmacokinetics of Major Anticancer Drugs
| Drug | Genotype | Mathematical association | Recommended dosing | Pharmacological relevance | References |
|---|---|---|---|---|---|
| Docetaxela | ABCB1 1236C>T | CL = 56.5·(1.0HETZ)·(0.72HOMZ) | – | 28% Lower drug clearance in homozygous mutant patients | (30) |
| Gemcitabine | CDA*3 | CL = 73·BSA·(1–0.64·HOMZ)·(1–0.17·HETZ) | – | 64% Lower CL in HOMZ 17% lower CL in HETZ | (78) |
| Gemcitabine | CDA*2 | CL = 171·(0.79HETZ)b | – | 21% Lower CL in HETZb | (91) |
| Imatinib | ABCG2-421 C > A | CL = 7.3·(WT/54)0.56·(AGP/1.13)−0.65·(ALB/38)0.66·0.77HETZb | No dose adaptation needed | 23% Lower CL in HETZb | (92) |
| Indisulam | CYP2C9*3 | CL = 46·(1–Θ1·HETZ + 2·Θ2·HOMZ) | 50–100 mg/m2 dose reduction | 27% Lower Vcmax | (29) |
| CYP2C19*3 | per mutated allele | 38% Lower CLc | |||
| Letrozoled | CYP2D6 | CL/F = 1.03·(WT·1 + HETZ·0.84 + HOMZ·0.45) | No dose adaptation needed | 14% Lower CL/F in HETZ | (93) |
| 55% Lower CL/F in HOMZ | |||||
| 6-MPe | TPMT*3A,3B,3 C | FM3 = 0.019·(2.56)TPMT | 40% dose reduction in HETZ | Overproduction of 6-TGN in the presence of TPMT*3A,3B,3 C | (94) |
| 90% dose reduction in HOMZ |
Ref reference, HOMZ homozyous mutant, HETZ HETZ heterozygous mutant, CL drug clearance (liters per hour), D dose, GFR glomerular filtration rate (ml/min/1.73 m2), VM EL maximum elimination capacity (μmol/h), 6-MP 6-mercaptopurine, TPMT thiopurine S-methyltransferase (presence of at least one TPMT gene mutation), FM 3 fractional metabolic transformation of 6-MP into 6-Thioguanine nucleotide (6-TGN)
aAnalysis performed in patients receiving 3-weekly docetaxel/paclitaxel
bNo homozygous mutant patients in this population
cFinal PK-model included linear (CL) and nonlinear Michaelis–Menten (V max) elimination (95)
dJapanese healthy postmenopausal women
eIn children with acute lymphoblastic leukemia