Phase 1 study of safety and tolerability of an oral contraceptive containing low-dose ethinyl oestradiol combined with glecaprevir/pibrentasvir treatment in healthy premenopausal women.

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.

Liver toxicity in oncology trials and beyond: a simplified concept for management of hepatocellular drug-induced liver injury in patients with abnormal baseline liver tests.

BACKGROUND: Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation. METHODS: We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines. RESULTS: The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively. CONCLUSIONS: Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.