A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871.
OBJECTIVE
Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients.


METHODS
We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done.


RESULTS
We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied.


CONCLUSIONS
Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.
Lewis
Lionel D
LD
Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, Dartmouth Medical School, The Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA. Lionel.D.Lewis@Dartmouth.edu
Miller
Antonius A
AA
Rosner
Gary L
GL
Dowell
Jonathan E
JE
Valdivieso
Manuel
M
Relling
Mary V
MV
Egorin
Merrill J
MJ
Bies
Robert R
RR
Hollis
Donna R
DR
Levine
Ellis G
EG
Otterson
Gregory A
GA
Millard
Frederick
F
Ratain
Mark J
MJ
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D044383:Black People; D015331:Cohort Studies; D016572:Cyclosporine / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000208:ethnology*; D027361:Organic Anion Transporters / Q000096:biosynthesis; D043823:Taxoids / Q000493:pharmacokinetics*; D044465:White People; D015262:Xenobiotics / Q000493:pharmacokinetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D027361:Organic Anion Transporters; D043823:Taxoids; D015262:Xenobiotics; D000077143:Docetaxel; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human