Significance of the biopharmaceutical properties of tramadol sustained-release formulations for chrono-pharmacologically optimized treatment of pain from various sources.
Tramadol is currently one of the most frequently used opioid analgesics in the world.


OBJECTIVE
The objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning intake of an extended-release pellet system designed for once daily administration. Moreover, the suitability of the preparation for chrono-adjusted pharmacotherapy was to be investigated.


METHODS
18 male and female volunteers were enrolled in the study and treated with 200 mg tramadol extended-release capsules, which were to be taken in the fasted state between 7:30 and 8:00 a.m. or p.m., respectively. The parent compound and its O-desmethyl-metabolite were analyzed in plasma samples using a LC-MS/MS procedure.


RESULTS
Maximum exposure of tramadol (geometric means of C(max)-values) was determined as 289.3 ng/ml after morning and 283.1 ng/ml after evening administration. Extent of tramadol exposure (geometric means of AUC(0-48)-values) was calculated as 4,802.5 ng x h/ml after morning and 4,767.0 ng x h/ml after evening administration. Also tmax-values were comparable after morning and evening administration (9.00 vs. 9.50 hours). Statistical analyses, based on conventional bioequivalence approach, revealed no evidence of any impact of the time-point of administration on the biopharmaceutical performance of the dosage form investigated here.


CONCLUSIONS
Bioavailability of the extended-release tramadol capsules for once daily administration is not affected by the time-point of administration. Total and maximum exposure of the product was bioequivalent after intake in the morning and at night. Thus, the time-point of administration may be adjusted to the patient's needs without any significant change in the in-vivo performance.
Warnke
A
A
SocraTec R&D GmbH, Oberursel, Germany. andre.warnke@socratec-pharma.de
Schug
B
B
Vanderbist
F
F
Erbist
Blume
H
H
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods*; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055870:Drug Chronotherapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*; D014147:Tramadol / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D014147:Tramadol