Coadministration of ritonavir strongly enhances the apparent oral bioavailability of docetaxel in patients with solid tumors.
OBJECTIVE
To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer.


METHODS
A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel.


RESULTS
The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 +/- 1.5 and 2.8 +/- 1.4 mg/h/L, respectively, compared with 1.9 +/- 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% +/- 90% and 161% +/- 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated.


CONCLUSIONS
Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.
Oostendorp
Roos L
RL
Department of Medical Oncology, Division of Clinical Pharmacology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. r.oostendorp@nki.nl
Huitema
Alwin
A
Rosing
Hilde
H
Jansen
Robert S
RS
Ter Heine
Rob
R
Keessen
Marianne
M
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001682:Biological Availability; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir