TABLE 1.

Trial design: doravirine drug interaction trials with EE-LNG, ritonavir, and ketoconazole^a

Trial	Trial design and description	Key inclusion and exclusion criteria		Treatment			Blood sampling
		Inclusion criteria	Exclusion criteria	Period 1	Period 2	General comments	Period 1	Period 2
CYP3A substrate: effects of multiple-dose doravirine on single-dose PK of an oral contraceptive, EE-LNG	Phase 1, open-label, two-period, fixed-sequence trial (protocol no. MK-1439-012); trial dates, 1 February 2013 to 1 April 2013; 20 women were enrolled, and 19 women completed the trial	Healthy women aged 18–65 yr; postmenopausal or oophorectomized; BMI = 18.5–32.0 kg/m2	Positive result for HIV, hepatitis B virus surface antigen, or hepatitis C virus infection; use of any drugs or substances known to be inducers of CYP enzymes and/or P-gp, including St. John’s wort, within 28 days or 5 times the half-life of the product (whichever was longer) prior to the first dose of trial drug or known to be significant inhibitors of CYP enzymes and/or significant inhibitors or substrates of P-gp, OATP, UGT, and/or SULT1E1 within 14 days or 5 times the half-life of the trial drug (whichever was longer) prior to the first dose of trial drug	Single dose of EE at 0.03 mg and LNG at 0.15 mg on day 1, followed by a 7-day washout period	Doravirine was administered at 100 mg QD on days 1–17 and was coadministered with EE at 0.03 mg and LNG at 0.15 mg on day 14	EE-LNG was administered in a fasted state (≥10 h predose and ≥4 h postdose); doravirine was administered in a fasted state (≥1 h predose and ≥2 h postdose), except on day 14, when it was coadministered with EE-LNG in the fasting state (≥10 h predose and ≥4 h postdose)	For samples for EE and LNG assay, predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 h postdose	For samples for EE and LNG assay, on day 14, predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 h postdose
CYP3A inhibitor: effects of multiple-dose ritonavir on single-dose PK of doravirine	Phase 1, open-label, fixed-sequence, two-period trial (protocol number MK-1439-002, EudraCT no. 2011-002722-48); trial dates, 16 August 2011 to 16 November 2011; 8 men were enrolled, and 8 men completed the trial	Healthy men aged between 18 and 50 yr; BMI ≤ 35 kg/m2	History of documented HIV infection; concomitant use of medications or herbal remedies beginning approximately 2 wk (or 5 half-lives) prior to initial dose of trial drug until the posttrial visit	Single dose of doravirine 50 mg (day 1), followed by a 7-day washout period	Ritonavir was administered at 100 mg twice daily on days 1–20 and was coadministered with a single dose of doravirine at 50 mg on the morning of day 14	Doravirine was administered in a fasted state (fasting for ≥8 h predose and 4 h postdose); ritonavir was administered within 30 min prior to or after a meal, except on day 14, when it was coadministered with doravirine in a fasted state (fasting ≥8 h predose and 4 h postdose)	Predose and at 0.5, 1, 2, 3, 4, 5, 6, 8 10, 12, 16, 24, 48, 72, 96, and 120 h postdose	Predose and at 0.5, 1, 2, 3, 4, 5, 6, 8 10, 12, 16, 24, 48, 72, 96, 120, 144, and 168 h postdose (day 14)
CYP3A inhibitor: effects of multiple-dose ketoconazole on single-dose PK of doravirine	Phase 1, open-label, two-period, fixed-sequence trial (protocol no. MK-1439-010; trial dates, 21 November 2012 to 31 December 2012; 8 men and 2 women were enrolled, and 8 men and 2 women completed the trial	Healthy men and women between 19 and 50 yr of age; women were required to be of nonchildbearing potential; BMI = 18.5–32.0 kg/m2	Positive result for HIV, hepatitis B virus surface antigen, or hepatitis C virus infection; use of any drugs or substances known to be significant inhibitors or inducers of CYP enzymes, significant inhibitors, inducers, or substrates of P-gp, or significant inhibitors or substrates of OATP within 14 days (for inhibitors/substrates) or 28 days (for inducers) or within 5 half-lives before the first trial drug dose	Single dose of doravirine 100 mg (day 1), followed by a ≥7-day washout period	Ketoconazole was administered at 400 mg QD on days 1–10 and was coadministered with doravirine at 100 mg on the morning of day 2	Doravirine was administered in a fasted state (fasting for ≥10 h predose and 4 h postdose); ketoconazole was administered in a fasted state (fasting for ≥1 h predose and ≥2 h postdose), except on day 2, when it was administered with doravirine in a fasted state (fasting for ≥10 h predose and 4 h postdose)	Predose and at 0.5, 1, 1.5, 2, 3, 6, 12, 24, 30, 48, and 72 h postdose	On day 2, predose and at 1, 1.5, 2, 3, 6, 12, 24, 48, 96, 144, and 216 h postdose

^aBMI, body mass index; CYP3A, cytochrome P450 3A; EE, ethinyl estradiol; HIV, human immunodeficiency virus; LNG, levonorgestrel; OATP, organic-anion-transporting polypeptide; PK, pharmacokinetic; QD, once daily.