In this pharmacokinetic drug-interaction study, co-administration with exenatide did not affect mean plasma AUC of EE and LV under single- or multiple-dose conditions. Furthermore, no decreases in trough concentrations were observed. Additionally, no substantive changes in PK profiles were observed when the OC was administered 1 hour before exenatide. A small effect was observed (90% CI; 0.78, 0.93) in Cmax
when OC was administered alone, however, as the lower confidence bound is close to 0.8, this shift is not likely to be of clinical relevance. Reductions in peak OC concentrations, accompanied by delayed Tmax
, were observed with OC administered 30 minutes after exenatide. This effect of exenatide on OC absorption would be expected, due to its action to slow gastric emptying, and is consistent with prior drug-drug interaction studies of exenatide with other orally administered drugs [8
Drug-drug interaction studies with oral contraceptives are generally conducted to understand the potential for concomitantly administered drugs to induce or inhibit cytochrome P450 isoenzyme (CYP) mediated oxidative metabolism of EE [16
]. While EE is metabolised by both CYP3A-mediated oxidative metabolism and Phase II metabolism, including glucuronidation and sulfation, the most clinically relevant metabolic pathway is induction or inhibition of CYP3A. Drugs that decrease EE bioavailability via CYP3A induction may potentially result in reduced OC efficacy. The observation that OC AUC concentrations were unaltered in this study confirmed that exenatide does not induce CYP3A. However, the clinical relevance of Cmax
reductions seen in the study (up to 46% for EE and 41% for LV) requires additional consideration.
Reports of large inter-subject variability in concentrations of OCs, with several-fold differences in serum concentrations likely due to inter-individual differences in first-pass metabolism, have been described in the literature. Goldzieher et al. [17
] have reported that differences in EE concentrations have been shown to vary between ethnic groups, as well as across study sites and, even for a given individual, EE AUCs can vary by almost a factor of 4. This same study group has also reported the existence of high intra- and inter-subject variability in the pharmacokinetics of progestins such as LV [17
]. Thus, the magnitude of Cmax
reduction observed in the present study was likely within the inherent PK variability of the OC components.
The current study did not measure OC pharmacodynamics (eg, follicle-stimulating hormone or luteinizing hormone concentrations); therefore, a direct within-study clinical relationship with the observed Cmax
reduction cannot be derived. Importantly, no break-through bleeding was reported. Break-through bleeding may be associated with low concentrations of estrogen-progestin [16
A review of prescription labeling indicates that drug interactions with OCs are deemed to be clinically important, and dosage adjustments are thereby recommended, only when associated with a significant reduction in OC AUC. However, there does not appear to be a well-accepted minimum threshold concentration for pharmacological activity. Importantly, in this study OC AUC was unchanged. Furthermore, trough concentrations did not decrease in the presence of exenatide suggesting that sub-therapeutic concentrations were unlikely.
In the absence of conclusive literature on the exposure-efficacy relationships of OCs, other aspects of OC PK/PD were considered to help understand the possible clinical relevance of the Cmax
decrease observed in the present study. In food-effect studies, OC Cmax
reductions of up to 40% are commonly observed without changes in AUC. Despite this potential effect of food on Cmax
, OCs are generally recommended to be taken without regard to food [19
], suggesting that PK changes observed in this study are not likely to be clinically relevant. In the current study, the effect of food consumption on the OC PK cannot be clearly differentiated from the effects of exenatide; however, these data reflect conditions under which the 2 drugs are likely to be co-administered, given that exenatide is to be administered within an hour of meals. Thus, in consideration of indirect evidence from food-effect studies, the large inherent variability in OC concentrations, and the fact that product labeling suggests changes in OC dosage only in the presence of large changes in OC AUC alone, we conclude that the PK changes observed in the present study are not likely to have clinical implications.
Concomitant administration of exenatide and a combination OC to healthy female subjects resulted in a high incidence of gastrointestinal adverse events. This study used 4-day dose initiation at 5 μg BID, rather than 4 weeks as recommended for exenatide dosing [20
], and this may have contributed to the poor tolerability. Furthermore, cross-study comparisons have suggested that exenatide administration may result in a higher incidence of gastrointestinal adverse events in healthy subjects compared with patients with type 2 diabetes [8
]. More specifically, the high incidence of nausea and vomiting observed in the present drug-drug interaction study has not been observed in large clinical trials of exenatide-treated patients with type 2 diabetes [21
]. Additionally, although there were no unexpected adverse events observed in this study, the incidence of skin-related adverse events among exenatide-treated subjects (53%) was higher than the incidence observed in previous clinical studies [21