Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy

Abstract

Background: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules.

Objectives: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo.

Methods: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug.

Results: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h.

Conclusion: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

Conflict of interest statement

PS-L, LZ-D, EG-A, and TV are employees of ITF Research Pharma S.L.U. MS-V, RR-J and JN-T are employees of Inibsa Ginecologia S.A.

© 2023. The Author(s).

Figures

Fig. 1

Cariban® modified-release hard capsules. Schematic view (left) and picture (right) displaying the product presentation

Fig. 2

In vitro dissolution profile of different type of release forms. Seven-h in vitro dissolution profile of doxylamine (A) and pyridoxine (B) active substances from immediate- (pink line), delayed- (black line), and prolonged-release (Cariban®, blue line) formulations. Below the graphs is a picture of the gastrointestinal tract parallelly disposed to the pH conditions used in the test to illustrate the mimicked anatomical region: acidic pH for the stomach and neutral pH for small intestine. The mean value ± SD of the percentage of actives dissolved over time is shown

Fig. 3

Plasma concentration–time curves for doxylamine and pyridoxine metabolites following Cariban® capsules administration under fasted conditions in healthy volunteers. A, B Full profile of plasmatic levels of doxylamine (A) and pyridoxine (B) for 432 h post-administration. C, D Data extracted from A and B showing the plasmatic level of doxylamine (C) and pyridoxine (D) zoomed on the first 10 h post-administration. Data are shown as mean concentration (ng/ml)/time (h)

Fig. 4

Predicted plasma concentration–time curves for doxylamine (A) and pyridoxine (B–D) metabolites following Cariban® administration posology. Simulation of the plasma concentrations of doxylamine enantiomers (A), pyridoxine (B), and the related metabolites pyridoxal (C) and pyridoxal 5′-phosphate (D), during the first 4 days following the posology instructions of the SmPC. The numbers in the graphs refer to the number of capsules taken at a given timepoint according to the progressive posology indicated in the SmPC. Shadowed boxes make up a whole-day (24 h) morning-to-night posology (i.e., capsules taken in the morning–afternoon–night). Data are shown as mean concentration (ng/ml)/time (h)