Ledipasvir/Sofosbuvir + Ethinylestradiol/Norgestimate = Unknown or no reaction

Study Design

German, et al, sought to determine the effect of Sofosbuvir (SOF) and Ledipasvir (LDV) on the pharmacokinetics of norgestimate (NGM)/ethinyl estradiol (EE) and to assess the effect of NGM/EE on the pharmacokinetics of SOF and LDV.In this open-label, fixed-sequence, 4 cycle, phase I study in 15 HCV-uninfected women of child-bearing potential. A Lead in Cycle was used to synchronize dosing schedule. All treatments were administered with a moderate fat meal. During the Lead in Cycle, patients received only NGM/EE (Ortho-Tri Cyclen Lo) on days 1-28 (NGM: 180 mcg, 215 mcg, 250 mcg EE: 25 mcg).During Cycle one, patients again received only NGM/EE for 28 days. During Cycle two, patients received NGM/EE on days 29-56 and received SOF on days 36-42. On Cycle 3, patients received NGM/EE on days 57-84 and received LDV on days 57-70. Pharmacokinetic sampling was performed over 24 hours. On day 14, NGM metabolites norelgestromin (NGMN) and norgestrel (NG) and ethinyl estradiol were sampled. On Day 42, NGMN, NG, EE, SOF and metabolites GS-566500 and GS-331007 were sampled. On Day 70, NGMN, NG, EE and LDV were sampled. Serum follicle-stimulating hormone, leuteinizing hormone and progesterone levels were measured in each cycle. Pharmacokinetic parameters of SOF and its metabolites as well as LDV were descriptively compared with historical data.

Study Results

EE Pharmacokinetics are described below:ParameterNGM/EENGM/EE + SOFGMR% (90% CI)NGM/EE + LDVGMR% (90% CI)AUC (pg*h/ml)662 (24)718 (23.2)109 (94-126)796 (23)120 (104, 139)Cmax (pg/ml)64.2 (23.7)74.5 (28.7)115 (96.6, 136)92.6 (36.7)140 (118, 166)Cmin (pg/ml)13.6 (38.2)13.2 (33.8)99 (79.7, 123)13.1 (34.1)98.3 (79.2, 122)Modest increases in EE Cmax (40%) noted with LDV, but the magnitude of change was similar to that observed with other drugs (data not shown). The authors suggested that this might be related to intestinal inhibition of drug transporters involved in the disposition of EE.NGMN Pharmacokinetics are described below:ParameterNGM/EENGM/EE + SOFGMR (90% CI)NGM/EE + LDVGMR (90% CI)AUC (pg*h/ml)17400 (26.5)18100 (21.9)106 (92.3, 121)17700 (21.3)103 (90.1, 118)Cmax (pg/ml)1670 (21.9)1800 (24.6)107 (92.6, 122)1710 (23.3)102 (89.2, 116)Cmin (pg/ml)428 (35.1)452 (31.9)107 (89.0, 128)462 (31.5)109 (91.2, 131)Pharmacokinetic parameters of NGMN were not altered by co administration with SOF or LDV. NG Pharmacokinetics are described blow:ParameterNGM / EENGM/EE + SOFGMR% (90% CI)NGM/EE + LDVGMR % (90% CI)AUC (pg*h/ml)43500 (30.6)51800 (31.3)119 (98.4, 145)43000 (32.6)99 (81.5, 120)Cmax (pg/ml)2240 (27.7)2640 (27.8)118 (99.2, 141)2310 (30)103 (86.5, 123)Cmin (pg/ml)1610 (32.8)1980 (35.2)123 (99.8, 151)1610 (34.2)100 (81.5, 123)Small increases in NG AUC (19%), and Cmin (23%) were noted with SOF, but the authors did not deem this to be clinically important. Pharmacokinetics of SOF, its metabolites and LDV are described below, and are within range of those reported in previous studies.ParameterSOFGS-566500GS-331007LDVAUC (ng*h /ml)829 (61.3)1000 (26.3)9910 (18.5)13300 (35.5)Cmax (ng / ml)671 (93.1)212 (27)1420 (31.7)699 (33.9)Cmin (ng/ ml)--------141 (19.9)513 (38)In all cycles, LH, FSH and progesterone median values were comparable across treatments and are consistent with oral contraception administration and absence of ovulation.

Study Conclusions

References

P German, L Moorhead, Pang PS, M Vimal, Mathias A. Lack of a clinically important pharmacokinetic interaction between norgestimate/ethinyl estradiol and sofosbuvir or ledipasvir in hcv-uninfected female subjects. (abstract 469). 64rd Annual Meeting Of The American Association For The Study Of Liver Diseases. Washington DC. ; 2013.