Pharmacokinetics (PK) of ethinylestradiol/levonorgestrel co-administered with atazanavir/cobicistat

Figures & data

Figure 1 Study design.

Table 1 Participant demographics, withdrawals and withdrawal reasons

ID	Age	Ethnicity	BMI	Group	Study stage reached	Reason for withdrawal
101	31	Hispanic	21.1	G1	Completed	N/A
102	27	White	23.7	G2	Between D7 and D14	Rash
103	30	African	29.3	G1	Completed	N/A
104	33	White	22.1	G2	Completed	N/A
105	30	African	26.8	G1	Between D28 and D35	Deranged LFTs
106	28	Turkish	23.1	G1	Before baseline	First dose not given
107	35	White	26.9	G1	Completed	N/A
108	23	White & black Caribbean	27.4	G2	Between D35 and D43	Moderate nausea, vomiting, orthostatic hypotension, diarrhoea
109	18	White	20.7	G2	Between Baseline and D7	Stopped taking study medication due to side effects, not specified
110	27	White	25.3	G2	Completed	N/A
111	19	White	19.0	G1	Completed	N/A
112	25	White & black Caribbean	22.4	G2	Between D35 and D43	No cause given
113	29	White	27.6	G1	Before baseline	First dose not given

ID = study identification, BMI = body mass index, G = group, D = day, n/a = not available.

Note: N/A: not applicable; G1: Group 1; G2: Group 2; D: day. Highlighted rows in gray = participants who completed the study. Drug sequences:

Group 1: EE/LNG (Microgynon) alone on days 1–21, EE/LNG (21 days) + ATV/COBI (14 days) in the co-administration phase (days 22–43) and ATV/COBI alone on days 43–56.

Group 2: ATV/COBI alone on days 1–21, EE/LNG (21 days) + ATV/COBI (14 days) in the co-administration phase (days 22–43) and EE/LNG alone on days 43–56.

Table 2 Summary of pharmacokinetic data for all four drugs

	GM Cmax (90%CI) (ng/mL)					GM AUC0-24 (90% CI) (ng*h/mL)					GM C24 (90% CI) (ng/mL)
	Alone	CV%	Combined	CV%	GMR	Alone	CV%	Combined	CV%	GMR	Alone	CV%	Combined	CV%	GMR
LNG (n = 6)
Total	6.5 (3.5–9.6)	60	5.4 (3.7–7.2)	43	0.83 (0.68–1.02)	92 (41–143)	67	84 (57–111)	43	0.92 (0.71–1.18)	2.83 (1.2–4.5)	67	2.85 (1.9–3.8)	45	1.01 (0.73–1.38)
Group 1 (n = 4)	8.8 (5.9–12)	46	7.2 (6.1–8.3)	23	0.82 (0.61–1.11)	130 (81–180)	50	111 (93–129)	23	0.85 (0.64–1.12)	4.2 (2.7–5.7)	47	3.8 (3.2–4.5)	25	0.90 (0.64–1.27
Group 2 (n = 2)	3.6 (1.5–5.7)	47	3.09 (2.1–4.1)	26	0.86 (0.66–1.12)	45 (3.2–87)	69	48 (36–61)	23	1.07 (1.74–2.69)	1.3 (–0.05 to 2.6)	75	2.6 (1.0–4.2)	59	0.9 (0.64–1.27)
EE (n = 6)
Total	40 (28–53) × 10^–3	43	42 (32–52) × 10^–3	34	1.05 (0.92–1.19)	407 (259–555) × 10^–3	49	410 (318–501) × 10^–3	32	1.01 (0.83–1.22)	7.4 (3–12) × 10^–3	72	5.6 (3.9–7.3) × 10^–3	42	0.75 (0.6–0.93)
Group 1 (n = 4)	43 (28–58) × 10^–3	47	46 (32–60) × 10^–3	35	1.07 (0.88–1.3)	446 (281–612) × 10^–3	50	440 (335–544) × 10^–3	33	0.98 (0.77–1.26)	8.2 (3–13) × 10^–3	76	5.5 (3.7–7.3) × 10^–3	45	0.67 (0.50–0.89)
Group 2 (n = 2)	36 (29–42) × 10^–3	26	36 (32–39) × 10^–3	15	1 (0.88–1.13)	338 (202–475) × 10^–3	55	356 (302–411) × 10^–3	22	1.05 (0.7–1.59)	6.1 (3.2–9) × 10^–3	63	5.7 (3.5–8) × 10^–3	53	0.94 (0.82–1.08)
ATV (n = 4)
Total	4157 (3151–5163)	39	3133 (2472–3795)	34	0.75 (0.60–0.95)	48998 (37387–60608)	38	38293 (27206–49380)	45	0.78 (0.64–0.96)	1061 (614–1507)	62	949 (527–1371)	66	0.89 (0.72–1.11)
Group 1 (n = 4)	4447 (2692–6201)	45	2861 (2158–3565)	29	0.64 (0.46–0.90)	49455 (35411–634500)	33	33680 (24048–43312)	32	0.68 (0.51–0.91)	930 (348–1510)	65	787 (543–1031)	35	0.85 (0.59–1.21)
Group 2 (n = 4)	3886 (2692–5080)	36	3432 (2286–4577)	38	0.88 (0.65–1.21)	48544 (27777–69312)	48	43539 (23393–63684)	50	0.90 (0.69–1.17)	1211 (467–1954)	65	1145 (341–1949)	71	0.95 (0.71–1.27)
COBI (n = 4)
Total	1760 (1604–1917)	15	1554 (1325–1782)	25	0.88 (0.8–0.97)	16456 (13863–19049)	26	14054 (10703–17405)	39	0.85 (0.77–0.95)	70 (27–113)	84	62 (13–112)	101	0.89 (0.66–1.21)
Group 1 (n = 4)	1810 (1669–1952)	9	1414 (1173–1655)	20	0.78 (0.7–0.87)	15834 (13044–18624)	21	11820 (9572–14069)	23	0.75 (0.65–0.86)	49 (25–73)	53	44 (26–61)	44	0.89 (0.47–1.67)
Group 2 (n = 4)	1712 (1409–2014)	21	1707 (1332–2082)	26	1 (0.95–1.05)	17102 (12363–21842)	32	16710 (10942–22479)	40	0.98 (0.91–1.05)	99 (21–177)	78	89 (–4.7 to 182)	94	0.90 (0.74–1.09)

EE = ethinylestradiol, LNG = levonorgestrel, ATV = atazanavir, COBI = cobicistat, CV = coefficient of variation, GM = geometric mean, GMR = geometric mean ratio, CI = confidence interval, C_max = maximum concentration, AUC_0-24h = area under the curve from 0 to 24 h, C_24h = concentration at 24 h postdose.

Figure 2 Levonogestrel (LNG) GM (95% CI) plasma concentration versus time curves, with and without ATV/COBI, GM (95%CI) n = 6.

Figure 3 Ethinylestradiol EE GM (95% CI) plasma concentration versus time curves, with and without ATV/COBI, GM (95%CI) n = 6.

Table 3 Summary of COCP drug interactions studies with atazanavir, ritonavir, and cobicistat

		ATV/COBI + EE/LNG (This study)	PI/RTV + NET^a (n = 16)	ATV/RTV + EE/NGM^b (n = 13)	TDF/FTC/EVG/COBI + EE/LNG^c (n = 20)	ATV/COBI + EE/DRSP^d (n = 14)
Progestogen	AUC	8%	50%	85%	110%	130% (AUC0-∞)
	Cmax	17%	33%	68%	60%	12%
	Cmin	1%	26%	102%	Not available	Not available
EE	AUC	1%	N/A	19%	20%	22% (AUC0-∞)
	Cmax	5%	N/A	16%	10%	18%
	Cmin	25%	N/A	37%	Not available	Not available

AUC = area under the curve; C_max = maximum concentration reached; C_min = trough concentration; ATV = atazanavir; COBI = cobicistat; EE = ethinylestradiol; LNG = levonogestrel; PI = protease inhibitor; RTV = ritonavir; NET: norethindrone; NGM = norgestimate; TDF = tenofovir; FTC = emtracitabine; EVG = elvitegravir; DRSP = drospirenone; N/A: not applicable.