TY - JOUR
T1 - Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours
AU - Vermunt, Marit A.C.
AU - de Weger, Vincent A.
AU - Janssen, Julie M.
AU - Lopez-Yurda, Marta I.
AU - Keessen, Marianne
AU - Thijssen, Bas
AU - Rosing, Hilde
AU - Huitema, Alwin D.R.
AU - Beijnen, Jos H.
AU - Marchetti, Serena
N1 - Funding Information:
The study was funded and ModraDoc006 tablets provided by Modra Pharmaceuticals BV. Modra Pharmaceuticals is a commercial pharmaceutical company that was founded as a spin-off of the Netherlands Cancer Institute. ModraDoc006/r is currently in clinical development as the lead product of Modra Pharmaceuticals.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/3
Y1 - 2021/3
N2 - Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)0–48, AUC0–inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC0–48 and AUC0–inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. ClinicalTrials.gov Identifier: NCT03147378, date of registration: May 10 2017.
AB - Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir. Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03. Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)0–48, AUC0–inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC0–48 and AUC0–inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity. Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. ClinicalTrials.gov Identifier: NCT03147378, date of registration: May 10 2017.
KW - Administration, Oral
KW - Aged
KW - Antineoplastic Agents/administration & dosage
KW - Area Under Curve
KW - Cross-Over Studies
KW - Cytochrome P-450 CYP3A Inhibitors/administration & dosage
KW - Diarrhea/chemically induced
KW - Diet, High-Fat
KW - Docetaxel/administration & dosage
KW - Drug Combinations
KW - Fasting
KW - Fatigue/chemically induced
KW - Female
KW - Food-Drug Interactions
KW - Humans
KW - Hypokalemia/chemically induced
KW - Male
KW - Middle Aged
KW - Neoplasms/drug therapy
KW - Ritonavir/administration & dosage
KW - Tablets
KW - Therapeutic Equivalency
UR - http://www.scopus.com/inward/record.url?scp=85100211344&partnerID=8YFLogxK
U2 - 10.1007/s40268-020-00336-x
DO - 10.1007/s40268-020-00336-x
M3 - Article
C2 - 33464545
AN - SCOPUS:85100211344
SN - 1174-5886
VL - 21
SP - 103
EP - 111
JO - Drugs in R and D
JF - Drugs in R and D
IS - 1
ER -