Abstract

Key Points

Introduction

Human immunodeficiency virus (HIV) infection continues to be a global concern. In 2017, nearly 37 million people worldwide were living with HIV, and 1.8 million people were newly diagnosed with the virus [1]. Current guidelines recommend that all individuals with HIV infection be treated with antiretroviral therapy [2, 3]. First-line three-drug regimens generally consist of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a third drug from another class, usually an integrase strand transfer inhibitor (InSTI) for most individuals with HIV initiating antiretroviral therapy; a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) may be given instead of an InSTI in certain clinical situations [2, 3]. Although many treatment options are available, multiple factors can reduce the appropriateness of certain therapies for some individuals, including viral resistance to antiretroviral drugs, tolerability and associated side effects, and drug–drug interactions (DDIs). Among NNRTIs, efavirenz has been associated with central nervous system-related adverse events (AEs) as well as significant DDIs, and rilpivirine has reduced efficacy in individuals with high baseline HIV RNA and a low CD4⁺ cell count [3].

Doravirine is a novel NNRTI designed to overcome the limitations of other drugs in the class [4, 5]. Doravirine is active in vitro against typical NNRTI-associated mutations that are susceptible to other NNRTIs and exhibits a low rate of resistance and a unique resistance pathway [6, 7]. In two pivotal non-inferiority phase III trials (DRIVE-FORWARD, ClinicalTrials.gov NCT02275780; DRIVE-AHEAD, ClinicalTrials.gov NCT02403674), doravirine, as part of a combination therapy, demonstrated robust antiretroviral efficacy and a favorable safety profile [4, 5]. Additionally, doravirine had an improved neuropsychiatric profile compared with efavirenz and a favorable lipid profile compared with efavirenz or darunavir [4, 5]. Based on these data, doravirine 100 mg administered orally once daily in combination with other antiretroviral agents, and as part of a three-drug single-tablet regimen with lamivudine (3TC) 300 mg and tenofovir disoproxil fumarate (TDF) 300 mg, is indicated for use in adults with HIV-1 infection [8, 9]. In the USA, it is indicated for those with no prior antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine (or to 3TC and TDF for the three-drug single-tablet regimen) [8, 9].

This article reviews the pharmacokinetics of doravirine and includes assessments of the potential effects of demographic factors and the DDI profile of doravirine.

Methods of Literature Search

All sponsor-conducted/funded and published phase I DDI, special population, and pharmacokinetic-profiling trials evaluating doravirine available at the time of writing are included in this review. The phase I trials include those in participants without HIV-1 and a single phase I trial in people living with HIV-1. In addition, this review includes published data from sponsor-conducted phase II and phase III trials, which evaluated safety and efficacy of doravirine in people living with HIV-1. All sponsor data were published in peer-reviewed journals. Details of each trial in this review, including design, sample size, treatments, and trial population, can be found in Table S1. In addition, the bounds of clinical relevance for doravirine based on the totality of the phase I, II, and III data are also discussed, which provide context for the effects on doravirine pharmacokinetics observed in DDI and special population trials.

Doravirine Pharmacokinetics

Doravirine is a drug with low intrinsic clearance (3.73 L/h following intravenous administration) [10]. Its volume of distribution of 60.5 L—which is slightly larger than the volume of body water—suggests that doravirine distributes into tissues [10]. Doravirine undergoes oxidative metabolism mediated primarily by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP3A5 [10]. In an absorption, metabolism, and excretion (AME) study of [¹⁴C]doravirine, the major circulating component in plasma was unchanged [¹⁴C]doravirine (75%); M9, a metabolite that results from oxidation of the triazolone ring of doravirine, was the most abundant metabolite in plasma, where it accounted for 12.9% of the drug-related material [10]. M9 was not active against HIV reverse transcriptase in vitro. In addition, M9 was the major metabolite excreted in urine and feces (~39% and~16% of absorbed dose, respectively). Other measurable metabolites in urine accounted for<5% of the absorbed dose. Only a small proportion of doravirine was excreted unchanged in urine (6.3–13%) [10, 11], and based on the mass balance and excretion of doravirine in the [¹⁴C] AME study, biliary excretion is anticipated to be minor. Thus, excretion of unchanged drug is not a major pathway in the elimination of doravirine [10].

Following administration of single oral doses of doravirine (6–1200 mg) to healthy men, doravirine is rapidly absorbed with a median time to maximum plasma concentration (T_max) of 1–4 h [11]. Plasma concentrations declined in a single exponential phase, with an apparent terminal half-life of 12–19 h (Fig. 1). Plasma area under the concentration–time curve from time zero to infinity (AUC_0–∞), maximum plasma concentration (C_max), and plasma concentration at 24 h post-dose (C₂₄) increased in a slightly less than dose-proportional manner over the 6–1200 mg dose range. Median time to steady state was~2 days, and mean area under the concentration–time curve from time zero to 24 h post-dose (AUC_0–24), C₂₄, and C_max accumulation ratios (geometric mean ratio [GMR] Day 10/Day 1) were 1.2–1.4 [11]. These data are consistent with the apparent terminal half-life and indicate time-independent pharmacokinetics. Multiple-dose pharmacokinetics are supportive of once-daily dosing of doravirine [11], and it has been shown that plasma concentrations following 7 days of once-daily dosing with 100 mg of doravirine are maintained above the half maximal effective concentration (IC₅₀) for inhibition of wild-type virus for 72 h after the final dose in adults without HIV infection [12].

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Fig. 1

Mean (±SD) doravirine plasma concentration–time profile following single oral dose administration of doravirine 100 mg in healthy individuals (N=24). The inset shows the same data plotted on a semi-log scale. SD standard deviation

The pharmacokinetics of doravirine in individuals with HIV-1 infection were similar to those in healthy individuals [13, 14]. Based on a population pharmacokinetic analysis of individuals with (n=959) and without (n=341) HIV-1 infection, individuals with HIV-1 infection receiving doravirine 100 mg once daily have a doravirine geometric mean (% coefficient of variation) AUC_0–24 of 37.8 μM·h (27.0%), C₂₄ of 930 nM (41.6%), and C_max of 2260 nM (18.4%) [14]. Corresponding steady-state AUC_0–24, C₂₄, and C_max in healthy individuals following administration of 100 mg once daily were 41.1 μM·h, 902 nM, and 2880 nM, respectively [15]. Therefore, findings from trials evaluating doravirine pharmacokinetics carried out in participants without HIV-1 infection are expected to be applicable to those with HIV infection.

Definition of the Bounds of Clinical Relevance

The term “bounds of clinical relevance” refers to the range of doravirine pharmacokinetic values relative to those associated with the recommended dose of 100 mg once daily at steady state where safety and efficacy are expected to be comparable to the clinical dose. When altered pharmacokinetic exposure of doravirine falls within these bounds, safety and efficacy are expected to be comparable to those of 100 mg once-daily doravirine. The definition of clinical relevance bounds for doravirine is based on demonstrated efficacy and safety in the phase I, IIb, and III trials, as described below.

Exposure–response analyses [14] of efficacy endpoints from the two phase III trials [4, 5] were used to identify the lower bound of clinical relevance for doravirine, which was defined with respect to steady-state C₂₄; maintenance of minimal effective trough levels is typically associated with efficacy for antiretroviral therapies [16]. Based on analyses for the proportion of individuals achieving HIV-1 RNA<50 copies/mL (virologic response) and occurrence of virologic failure at week 48, both exposure–response relationships were generally flat over the entire range of doravirine steady-state C₂₄ values from the phase III trials, except for a slight decrease in efficacy in individuals with the lowest 10% of doravirine steady-state C₂₄ values [14]. Above the tenth percentile of doravirine steady-state C₂₄ values, there were no meaningful changes in the exposure–response relationships for virologic response and failure across the entire range of doravirine steady-state C₂₄ values [14]. The observed exposure–response trends in the first decile of doravirine steady-state C₂₄ values were likely driven by individuals with lower adherence, and therefore lower efficacy rates, rather than reflecting a true decrease in response at lower exposures. In fact, flat exposure– and dose–response relationships were observed over the 25–200 mg once-daily dose range in the phase IIb trial [14]. Nevertheless, the tenth percentile of doravirine steady-state C₂₄ values observed in phase III, corresponding to a 40% decrease in doravirine C₂₄, was set as a conservative lower bound for clinical relevance with respect to efficacy. Steady-state C₂₄ values above this bound are expected to correspond to efficacy similar to the 100 mg once-daily dose.

A 40% decrease in doravirine C₂₄ also corresponds approximately to the C₂₄ values associated with the 50 mg once-daily dose and is nearly twice the C₂₄ associated with the 25 mg once-daily dose [14], which were studied in the phase IIb trial and had efficacy similar to 100 mg once daily [17]. Even at this decreased C₂₄, doravirine plasma concentrations exceed the pharmacokinetic target of 78 nM, which is greater than 6-fold the in vitro IC₅₀ for inhibition of wild-type virus, and exceeds IC₅₀ values for common single resistance mutations (K103N, Y181C, G190A), and of the K103N/Y181C double mutant [16, 18, 19].

Steady-state AUC was selected as the exposure measure from which to judge clinical relevance from a safety perspective, as this parameter is an integration of concentrations over the 24-h dosing interval in which individuals are exposed to doravirine at steady state. In phase I trials, there was no evidence that the incidence of overall AEs or specific AEs was temporally associated with doravirine T_max [11, 15, 20–31], therefore suggesting that C_max does not play a major role in safety or tolerability. In the phase IIb trial, there was no evidence of exposure- or dose-related toxicities across the range of 25–200 mg doses evaluated, and no meaningful association between doravirine steady-state exposure and the incidence of neuropsychiatric AEs or fasting lipid levels that would further limit the exposure of doravirine from a safety perspective [17].

Concomitant use of moderate and strong CYP3A inhibitors, which are expected to be associated with 2- to 3-fold higher doravirine exposures relative to the 100 mg once-daily dose, were not prohibited in the pivotal phase III DRIVE-FORWARD trial [5]; however, they were prohibited in the DRIVE-AHEAD trial due to potential interactions with the comparator regimen [4]. In the phase III trials, the 100 mg once-daily dose was generally well tolerated and no treatment-related AEs of concern were identified [4, 5].

For doravirine steady-state exposures at least 3-fold those observed with the 100 mg once-daily dose in the phase III trials, there were no safety signals in short-term clinical pharmacology trials. Specifically, multiple doses of up to 750 mg once daily for 10 days and single doses of up to 1200 mg doravirine [11] were generally well tolerated and provided exposure multiples of~3.7- and~6.5-fold, respectively, relative to the steady-state AUC values observed following administration of 100 mg once-daily doravirine. In addition, a single dose of 1200 mg doravirine had no clinically meaningful effect on QTc values [32] at~4.3- and~3.3-fold exposure multiples to C_max and AUC_0–24, respectively. Thus, based on the totality of clinical experience for doravirine, increases in exposure up to~3-fold are not clinically meaningful.

Effect of Demographic Factors

The effects of demographic factors including age, gender, hepatic impairment, and renal impairment on doravirine pharmacokinetics were evaluated in dedicated phase I trials in participants without HIV-1 infection [22, 24, 25]. In addition, a population pharmacokinetic analysis of individuals with (n=959) and without (n=341) HIV-1 infection was conducted across the phase I, II, and III trials to evaluate the effects of these factors—as well as body weight, body mass index (BMI), race, or ethnicity—on doravirine pharmacokinetics [14].

Age

Physiological changes that occur with aging can result in altered drug pharmacokinetics in older compared with younger people [33]. As the population of people living with HIV-1 is aging [34], evaluation of doravirine in the older population was essential.

The effect of age on doravirine pharmacokinetics was investigated in a phase I trial of healthy elderly men and women (aged 65–80 years) compared with healthy young men and women (18–50 years); results showed that age did not have a clinically meaningful effect on the pharmacokinetics of doravirine among these age groups as the observed changes in AUC_0–∞, C_max, and C₂₄ were<20% [22] (Table 1, Fig. 2). Similarly, in a population pharmacokinetic analysis [14], although age was identified as a significant covariate for doravirine clearance (AUC_0–24 was 30% higher for individuals with HIV-1 infection aged≥65 years compared with those aged<65 years), the effect was consistent with the observations from the phase I trial, and not clinically meaningful as the increase falls within the clinical bounds described above. Similar findings were previously identified for other HIV treatments, where it was reported that age did not have a clinically relevant effect on the pharmacokinetics of boosted darunavir, dolutegravir, and lamivudine in people living with HIV, though boosted darunavir exposure was modestly increased in older people [35].

Table 1

Summary of the effect of demographic factors/disease/food on doravirine pharmacokinetics

Factor	Dosing	Comparison	Doravirine GMR (90% CI)				Reference
			AUC0–∞	AUC0–24	Cmax	C24
Age	Doravirine 100 mg SD	Elderly men/young men	0.85 (0.67–1.10)	–	0.92 (0.73–1.16)	0.81 (0.59–1.11)	[22]
	Doravirine 100 mg SD	Elderly women/young women	0.97 (0.79–1.19)	–	1.18 (0.98–1.42)	0.94 (0.72–1.21)	[22]
Gender	Doravirine 100 mg SD	Women/men	1.20 (1.03–1.40)	–	1.42 (1.23–1.64)	1.02 (0.84–1.24)	[22]
Hepatic impairment	Doravirine 100 mg SD	Moderate hepatic impairment/normal hepatic function	0.99 (0.72–1.35)	0.93 (0.74–1.18)	0.90 (0.66–1.24)	0.99 (0.74–1.33)	[25]
Renal impairment	Doravirine 100 mg SD	Severe renal impairment/normal renal function	1.43 (1.00–2.04)	–	0.83 (0.61–1.15)	1.38 (0.99–1.92)	[24]
Food	Doravirine 100 mg SD	Fed/fasted	1.16 (1.06–1.26)	–	1.03 (0.89–1.19)	1.36 (1.19–1.55)	[23]
	Doravirine 100 mg/lamivudine 300 mg/TDF 300 mg SD	Fed/fasted	1.10 (1.01–1.20)	–	0.95 (0.80–1.12)	1.26 (1.13–1.41)	[23]

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AUC_0–24 area under the concentration–time curve from time zero to 24 h, AUC_0–∞ area under the concentration–time curve from time zero to infinity, C₂₄ plasma concentration 24 h post-dose, CI confidence interval, C_max maximum plasma concentration, GMR geometric mean ratio, SD single dose, TDF tenofovir disoproxil fumarate

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Fig. 2

Visual summary of the effect of demographic factors/disease/food on doravirine exposure. Modified from Yee et al. [14]. Copyright © American Society for Microbiology, Antimicrob Agents Chemother, vol 63, 2019, e02502–18, DOI 10.1128/AAC.02502-18. 3TC lamivudine, AUC area under the concentration–time curve, BMI body mass index, C₂₄ plasma concentration 24 h post-dose, C_max maximum plasma concentration, CI confidence interval, GMR geometric mean ratio, HI hepatic impairment, popPK population pharmacokinetics, ref reference value, RI renal impairment, TDF tenofovir disoproxil fumarate. Shaded region represents the clinical bounds

Pharmacokinetics in Special Populations

Food Effects

The NNRTIs etravirine and rilpivirine are recommended to be taken following and with a meal, respectively; exposure to each of these drugs is substantially decreased in a fasted versus a fed state [43, 44]. To investigate the effect of food on doravirine pharmacokinetics, doravirine was administered following a fast and following a high-fat, high-calorie meal, both alone and as part of a single-tablet regimen combined with 3TC and TDF [23]. Although doravirine AUC_0–∞ and C₂₄ were slightly increased in the fed state compared with fasted state, by 10–36%, these changes were not considered clinically meaningful (Table 1, Fig. 2), suggesting doravirine may be administered with or without food [23]. In both phase III trials, doravirine was administered without regard to meals [4, 5].

In Vitro Drug–Drug Interaction (DDI) Assessment

In vitro assessment confirmed that oxidative metabolism of doravirine is mediated mainly by CYP3A4, with some minor contribution by CYP3A5 [10]. As a result, doravirine pharmacokinetics may be altered in the presence of CYP3A modulators. Doravirine did not inhibit the activity of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, or uridinediphosphate glucuronosyltransferase (UGT)1A1 (IC₅₀>100 μM for all enzymes) [45], at concentrations well above the doravirine mean peak plasma concentration of 2.26 μM, which corresponds to a maximal unbound concentration of 0.54 μM. Additionally, doravirine does not induce CYP1A2 or CYP2B6 mRNA or enzyme activity in vitro [45], and although a low level of CYP3A4 mRNA induction was observed with 10 μM doravirine, no effect on CYP3A4 enzyme activity was observed and it was projected to have no clinically meaningful impact [45]. Doravirine is a substrate of P-gp in vitro; however, P-gp does not appear to have a significant role in the disposition of doravirine [10]. Doravirine is not a substrate of the breast cancer receptor protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, or OATP1B3 [45], and, since renal excretion is not a major route of elimination of doravirine, it is therefore not likely to be affected by modulation of major hepatic or renal drug transporters [10]. In addition, doravirine is unlikely to cause DDIs via inhibition of major drug transporters, including P-gp, OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, MATE2K, and bile salt extrusion pump (BSEP) [45]. Systemic exposure to doravirine is not likely to cause DDIs via inhibition of BRCP; however, with an IC₅₀ value of 51 μM, inhibition of intestinal BCRP by doravirine is possible [45].

In Vivo DDI Assessment

Polypharmacy in individuals with HIV infection is common, and co-administration of antiretroviral drugs with drugs for treating co-morbidities of HIV-1 infection is often required, leading to the potential for DDIs [46]. One study estimated that potential DDIs occurred in approximately two-thirds of people receiving antiretroviral therapy for HIV infection; around one-quarter of these potential interactions were between antiretroviral medications themselves [46]. Common co-morbidities in individuals with HIV infection that require treatment include hepatitis C virus (HCV) infection, tuberculosis, diabetes, and hyperlipidemia [1, 38, 47].

The following sections discuss the clinical investigations of potential DDIs between doravirine and a range of drug classes likely to be co-administered, including concomitant antiretroviral drugs and medications for treating common co-morbidities. These findings are also extrapolated to other medications on the basis of known pharmacokinetic characteristics.

Doravirine and Antiretroviral Drugs for the Treatment of HIV Infection

Doravirine and Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

To support the development of a single-tablet regimen with doravirine, two DDI trials were conducted with doravirine and two commonly used NRTIs, 3TC and TDF [31]. 3TC and tenofovir are primarily eliminated via organic cationic secretion, glomerular filtration, and active tubular secretion, pathways that are not affected by doravirine [48, 49]. Neither NRTI is expected to affect CYP metabolism [48, 49]. Consistent with the disposition of all three agents, the DDI trials demonstrated no clinically meaningful effect on doravirine, tenofovir, or 3TC pharmacokinetics (Tables 2 and ​and3,3, Figs. 3 and ​and4),4), supporting co-administration without the need for dose adjustment [31] and the co-formulation of these agents into a single-tablet regimen.

Table 2

Summary of doravirine drug–drug interactions: the effect of concomitant drugs on doravirine pharmacokinetics

Concomitant medication dosing	Doravirine dosing	Doravirine GMR (90% CI) [(doravirine+concomitant medication)/doravirine alone]				Reference
		AUC0–∞	AUC0–24	Cmax	C24
TDF 300 mg once daily	Doravirine 100 mg SD	0.95 (0.80–1.12)	–	0.80 (0.64–1.01)	0.94 (0.78–1.12)	[31]
TDF 300 mg+lamivudine 300 mg	Doravirine 100 mg SD	0.96 (0.87–1.06)	–	0.97 (0.88–1.07)	0.94 (0.83–1.06)	[31]
Efavirenz prior dosing 600 mg once daily	Doravirine 100 mg SD (Day 1 following efavirenz cessation)	–	0.38 (0.33–0.45)	0.65 (0.58–0.73)	0.15 (0.10–0.23)	[15]
Efavirenz prior dosing 600 mg once daily	Doravirine 100 mg once daily (Day 14 following efavirenz cessation)	–	0.68 (0.58–0.80)	0.86 (0.77–0.97)	0.50 (0.39–0.64)	[15]
Ritonavir 100 mg once daily	Doravirine 50 mg SD	3.54 (3.04–4.11)	–	1.31 (1.17–1.46)	2.91 (2.33–3.62)	[26]
Dolutegravir 50 mg once daily	Doravirine 200 mg once daily	–	1.00 (0.89–1.12)	1.06 (0.88–1.28)	0.98 (0.88–1.09)	[20]
Elbasvir 50 mg+grazoprevir 200 mg once daily	Doravirine 100 mg once daily	–	1.56 (1.45–1.68)	1.41 (1.25–1.58)	1.61 (1.45–1.79)	[27]
Ledipasvir 90 mg/sofosbuvir 400 mg SD	Doravirine 100 mg SD	1.15 (1.07–1.24)	–	1.11 (0.97–1.27)	1.24 (1.13–1.36)	[27]
Ketoconazole 400 mg once daily	Doravirine 100 mg SD	3.06 (2.85–3.29)	–	1.25 (1.05–1.49)	2.75 (2.54–2.98)	[26]
Rifampin 600 mg once daily	Doravirine 100 mg SD	0.12 (0.10–0.15)	–	0.43 (0.35–0.52)	0.03 (0.02–0.04)	[74]
Rifabutin 300 mg once daily	Doravirine 100 mg SD	0.50 (0.45–0.55)	–	0.99 (0.85–1.15)	0.32 (0.28–0.35)	[75]
Maintenance methadone 20–200 mg once daily	Doravirine 100 mg once daily	–	0.74 (0.61–0.90)	0.76 (0.63–0.91)	0.80 (0.63–1.03)	[30]
Antacid oral suspension (1600 mg aluminum hydroxide/1600 mg magnesium hydroxide/160 mg simethicone) SD	Doravirine 100 mg SD	1.01 (0.92–1.11)	–	0.86 (0.74–1.01)	1.03 (0.94–1.12)	[28]
Pantoprazole 40 mg once daily	Doravirine 100 mg SD	0.83 (0.76–0.91)	–	0.88 (0.76–1.01)	0.84 (0.77–0.92)	[28]

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AUC_0–24 area under the concentration–time curve from time zero to 24 h, AUC_0–∞ area under the concentration–time curve from time zero to infinity, C₂₄ plasma concentration 24 h post-dose, CI confidence interval, C_max maximum plasma concentration, GMR geometric mean ratio, SD single dose, TDF tenofovir disoproxil fumarate

Table 3

Summary of doravirine drug–drug interactions: the effect of doravirine on the pharmacokinetics of concomitant drugs

Concomitant medication dosing	Doravirine dosing	Concomitant medication GMR (90% CI) [(doravirine+concomitant medication)/concomitant medication alone]				Reference
		AUC0–∞	AUC0–24	Cmax	C24
TDF 300 mg SD+lamivudine 300 mg SD	Doravirine 100 mg SD	Tenofovir:
		1.11 (0.97–1.28)	–	1.17 (0.96–1.42)	–	[31]
		Lamivudine:
		0.94 (0.88–1.00)	–	0.92 (0.81–1.05)	–	[31]
Midazolam 2 mg SD	Doravirine 120 mg once daily	0.82 (0.70–0.97)	–	1.02 (0.81–1.28)	–	[11]
Dolutegravir 50 mg once daily	Doravirine 200 mg once daily	–	1.36 (1.15–1.62)	1.43 (1.20–1.71)	1.27 (1.06–1.53)	[20]
Elbasvir 50 mg once daily+grazoprevir 200 mg once daily	Doravirine 100 mg once daily	Elbasvir:
		–	0.96 (0.90–1.02)	0.96 (0.91–1.01)	0.96 (0.89–1.04)	[27]
		Grazoprevir:
		–	1.07 (0.94–1.23)	1.22 (1.01–1.47)	0.90 (0.83–0.96)	[27]
Ledipasvir 90 mg/sofosbuvir 400 mg SD	Doravirine 100 mg SD	Ledipasvir:
		0.92 (0.80–1.06)	–	0.91 (0.80–1.02)	–	[27]
		Sofosbuvir:
		1.04 (0.91–1.18)	–	0.89 (0.79–1.00)	–	[27]
		GS-331007:
		1.03 (0.98–1.09)	–	1.03 (0.97–1.09)	–	[27]
Metformin 1000 mg SD	Doravirine 100 mg once daily	0.94 (0.88–1.00)	–	0.94 (0.86–1.03)	–	[29]
Atorvastatin 20 mg SD	Doravirine 100 mg once daily	0.98 (0.90–1.06)	–	0.67 (0.52–0.85)	–	[21]
Maintenance methadone 20–200 mg once daily	Doravirine 100 mg once daily	(R)-methadone:
		–	0.95 (0.90–1.01)	0.98 (0.93–1.03)	0.95 (0.88–1.03)	[30]
		(S)-methadone:
		–	0.98 (0.90–1.06)	0.97 (0.91–1.04)	0.97 (0.86–1.10)	[30]
		Total methadone:
		–	0.96 (0.90–1.03)	0.98 (0.92–1.03)	0.96 (0.87–1.05)	[30]
Ethinyl estradiol 0.03 mg/levonorgestrel 0.15 mg SD	Doravirine 100 mg once daily	Ethinyl estradiol:
		0.98 (0.94–1.03)	–	0.83 (0.80–0.87)	–	[26]
		Levonorgestrel:
		1.21 (1.14–1.28)	–	0.96 (0.88–1.05)	–	[26]

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AUC_0–24 area under the concentration–time curve from time zero to 24 h, AUC_0–∞ area under the concentration–time curve from time zero to infinity, C₂₄ plasma concentration 24 h post-dose, CI confidence interval, C_max maximum plasma concentration, GMR geometric mean ratio, SD single dose, TDF tenofovir disoproxil fumarate

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Fig. 3

Visual summary of doravirine DDIs: the effect of concomitant drugs on doravirine exposure. AUC area under the concentration–time curve, C₂₄ plasma concentration 24 h post-dose, C_max maximum plasma concentration, CI confidence interval, DDI drug–drug interaction, GMR geometric mean ratio, ref reference value, SD single dose, TDF tenofovir disoproxil fumarate. Shaded region represents the clinical bounds

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Fig. 4

Visual summary of doravirine DDIs: the effect of doravirine on the exposure of concomitant drugs. AUC, area under the concentration–time curve, C_max maximum plasma concentration, CI confidence interval, DDI drug–drug interaction, GMR geometric mean ratio, ref reference value, SD single dose, TDF tenofovir disoproxil fumarate

Abacavir and emtricitabine have no known interactions with CYP3A [3]. Abacavir is known to be a substrate of UGT1A1 and alcohol dehydrogenase, neither of which are likely to be impacted by doravirine [45]. Hence, interactions of abacavir or emtricitabine with doravirine are unlikely. Doravirine is not expected to cause any significant interactions with P-gp, BCRP, OATP1B1, and OATP1B3 [45], for which tenofovir alafenamide (TAF) is a substrate [50]. As the prescribing information for TAF does not suggest that it inhibits or induces CYP3A (TAF did not affect the pharmacokinetics of the sensitive CYP3A substrate midazolam) [50], a DDI with doravirine is not expected, and therefore doravirine and TAF may be co-administered. Furthermore, phase III trials have demonstrated the safety and efficacy of doravirine when co-administered with TDF and 3TC, or with other NRTIs such as emtricitabine, TAF, or abacavir [4, 5].

Doravirine and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Due to associated psychiatric and central nervous system effects of the NNRTI efavirenz [51], doravirine may be a suitable alternative for individuals who have difficulties tolerating efavirenz. Efavirenz is a known CYP3A inducer, and in order to maintain viral suppression during regimen switch, the interaction of doravirine with residual efavirenz concentrations and the persistent CYP3A4 induction effects following cessation of efavirenz [52] should be considered. Doravirine exposure was transiently decreased in the days following a switch from efavirenz to doravirine in healthy adults (Table 2, Fig. 3) [15]. Following discontinuation of efavirenz, efavirenz concentrations exceeded the therapeutic threshold (1000 ng/mL [53]) until Day 3, and at this time doravirine concentrations exceeded the pharmacokinetic target for efficacy (six times the IC₅₀) [15]; however, doravirine concentrations remained below the bounds for clinical efficacy through Day 14. Nevertheless, during this transient decrease in doravirine concentrations, dose adjustment is not considered necessary as individuals with HIV-1 infection are expected to be virologically suppressed prior to switch and will continue to receive other antiretroviral agents during switch, which supports the low likelihood of viral rebound or development of viral resistance [15]. Switching to a doravirine-based regimen was assessed in a phase III trial (DRIVE-SHIFT; ClinicalTrials.gov NCT02397096) that evaluated switching from a stable antiretroviral regimen to a single-tablet regimen of doravirine 100 mg with 3TC 300 mg and TDF 300 mg (DOR/TDF/3TC) [54]. In this trial, a similar high level of antiretroviral efficacy of DOR/3TC/TDF was observed in participants who switched from an efavirenz-based regimen and those who switched from another baseline regimen, showing that the transient decrease in doravirine concentration is not clinically meaningful [55].

As doravirine was shown not to be a significant inducer or inhibitor of a number of CYP enzymes in vitro [45], and in vivo doravirine did not significantly impact the pharmacokinetics of midazolam (Table 3) [11], doravirine is not expected to cause clinically meaningful DDIs with etravirine, which is a substrate for CYP3A, CYP2C9, and CYP2C19 enzymes [43], or with nevirapine, which is a substrate for CYP3A and CYP2B6 enzymes [56]. Etravirine and nevirapine are also inducers of CYP3A4 [3]. Based on the transient reduced exposure of doravirine following switch from efavirenz (a CYP3A inducer) [15], there is potential that switch from etravirine or nevirapine would result in a minor inductive effect on doravirine pharmacokinetics. However, based on the shorter half-lives of these agents [43, 51, 56], it is unlikely that the duration of effect would exceed that of efavirenz, and therefore switch from etravirine or nevirapine to doravirine is also supported. Rilpivirine does not induce or inhibit CYP3A4, and although it is a substrate for CYP3A4 [3], it is unlikely to result in DDIs with doravirine, similar to other CYP3A substrates [26].

Doravirine and HIV-1 Boosted and Unboosted Protease Inhibitors (PIs)

Ritonavir is an HIV-1 PI commonly used as a pharmacokinetic-enhancing agent for other HIV-1 drugs metabolized by CYP3A4, including other PIs [3, 57]. Because it is a strong CYP3A4 inhibitor, ritonavir increases the exposure of drugs—and “boosts” activity—via inhibition of CYP3A4-mediated drug metabolism [57]. Although ritonavir is not anticipated to be used as a pharmacokinetic enhancer for doravirine, the interaction between ritonavir and doravirine was evaluated in the event that doravirine is administered as part of a boosted-PI regimen or used concomitantly with other strong CYP3A inhibitors. Co-administration of doravirine and ritonavir increased doravirine exposure~ 3-fold compared with doravirine alone (Table 2, Fig. 3), consistent with the inhibition of CYP3A4 metabolism, the primary clearance pathway of doravirine [10, 26]. However, C_max increased only by~30%. In accordance with the clinical bounds described above, these changes in doravirine pharmacokinetics were not considered clinically meaningful, and no dose adjustment is required for co-administration of doravirine and ritonavir [26].

Cobicistat is a strong CYP3A inhibitor used as a pharmacokinetic enhancer for the PIs atazanavir and darunavir [58]. As the CYP3A inhibitor effect is expected to be similar to ritonavir [59], a~3 fold increase in doravirine exposure is expected when the two agents are co-administered.

Several other HIV-1 boosted or unboosted PIs have potential for perpetrating DDIs through modulation of various enzymes and/or transporters, including CYP3A, OATP, UGT1A1, and P-gp [3]. However, the magnitude of CYP3A inhibition for atazanavir, darunavir, indinavir, and saquinavir is not likely to be greater than that observed for ritonavir, and lopinavir is not a CYP3A inhibitor [59]. Therefore, these agents are unlikely to have a clinically meaningful effect on doravirine pharmacokinetics, despite being CYP3A4 substrates and/or inhibitors [3]. While lopinavir is considered a moderate inducer when given alone, it is only available for use in combination with ritonavir, and in this setting boosted lopinavir behaves as a CYP3A4 inhibitor, in addition to being a CYP3A4 substrate [3]. Similarly, while tipranavir is considered a CYP3A4 inducer, it is only recommended for use with ritonavir, and the net effect of these two agents is CYP3A4 inhibition [3]. As doravirine may be concomitantly administered with strong CYP3A inhibitors without dose adjustment [26], a dose adjustment would not be required for boosted tipranavir. Fosamprenavir, the prodrug of amprenavir, is considered a moderate CYP3A inhibitor and weak inducer [3], and therefore the net effect on doravirine exposure following co-administration is unknown. However, if this agent is used in combination with a pharmacokinetic enhancer, it is likely that there would be a net increase in doravirine exposure.

Doravirine and Integrase Strand Transfer Inhibitors (InSTIs)

In some instances, an NNRTI may be co-administered with an InSTI [3], and the combination of NNRTIs and InSTIs may offer an alternative to NRTI-based therapies [60]. Dolutegravir has shown good efficacy and tolerability along with a high barrier to resistance [20]; in vitro, low potential for DDIs was reported [61]. It is metabolized by UGT1A1/1A3/1A9 and CYP3A4, and is a substrate for P-gp and BCRP [61]. Although a weak inhibitor of CYP3A in vitro, dolutegravir does not inhibit or induce CYP3A in vivo [62]. In line with this finding, the pharmacokinetics of doravirine (200 mg once daily) in healthy subjects were shown to be similar in the presence or absence of dolutegravir (50 mg once daily) (Table 2, Fig. 4) [20]. The modest increases in dolutegravir AUC_0–24, C_max, and C₂₄ observed at a supratherapeutic doravirine dose of 200 mg once daily, thought to result from inhibition of BCRP in the gut by doravirine, were considered not clinically meaningful (Table 3, Fig. 4) [20].

Other InSTIs are unlikely to interact with doravirine based on their known metabolism or elimination pathways and their propensity to modulate major CYPs and transporters. For example, elvitegravir is a UGT1A1 and CYP3A4 substrate and CYP2C9 inhibitor, while raltegravir is a UGT1A1 substrate [3]; therefore, neither drug is likely to affect CYP3A-mediated metabolism of doravirine via induction or inhibition of CYP3A4. Elvitegravir may be boosted with either cobicistat or ritonavir [3] and, as discussed above, the increases in doravirine expected with these agents are not considered clinically meaningful.

Clinical Perspective

The population living with HIV is clinically and demographically diverse and has changed over time [1, 34, 38]. The presence of co-morbidities has increased in recent years [38], and with it comes the likelihood of polypharmacy and potential for DDIs with antiretroviral drugs [46]. The success of antiretroviral therapy has led to improvements in life expectancy, resulting in an aging population living with HIV [34]. Chronic kidney disease [41], hepatic disease [39], and cardiovascular disease [38] are complications commonly experienced by people living with HIV, so consideration of these populations may be particularly important. Doravirine is a novel NNRTI that has pharmacokinetic properties that support once-daily administration and address the complex HIV patient population needs. The clinical trials and population pharmacokinetic analysis described here support the use of doravirine across a wide range of populations with HIV-1 infection: age, gender, race, ethnicity, weight/BMI, renal function, and moderate hepatic impairment did not have an appreciable effect on doravirine pharmacokinetics, nor did food (fed or fasted) have a clinically meaningful impact [14, 22–25].

Doravirine was shown to have limited potential for clinically meaningful DDIs based on data obtained from in vitro studies of drug-metabolizing enzymes and drug transporters [10, 45] and clinical studies [15, 20, 21, 26–31]. Since doravirine is a substrate of CYP3A4 [10], the most likely route of its involvement in DDIs is via inhibition and induction of CYP3A activity by strong and moderate CYP3A inhibitors/inducers. CYP3A inhibition does not result in a clinically meaningful change in doravirine pharmacokinetics, and doravirine can be co-administered with these agents without dose adjustment. However, moderate and strong CYP3A inducers reduced doravirine exposure. For strong inducers, the magnitude of the decrease may impact efficacy; therefore, doravirine is contraindicated for use with any strong CYP3A inducer (e.g., rifampin, mitotane, avasimibe, phenytoin, carbamazepine, and enzalutamide) [8, 9, 74]. Similar restrictions for rifampin are also in place for other antiretroviral medications, including all PIs and several NNRTIs (including etravirine, nevirapine, and rilpivirine) [3]. TAF and cobicistat-boosted elvitegravir are contraindicated for both rifampin and rifabutin [3]. Dose adjustment of doravirine is recommended for the moderate inducer rifabutin [75]. As the magnitude of induction associated with CYP3A moderate inducers varies across compounds (e.g., etravirine, nevirapine, bosentan, nafcillin, and modafinil), and is also dependent on the substrate, the effect of other moderate inducers on the pharmacokinetics of doravirine cannot easily be predicted. However, if co-administration with moderate inducers cannot be avoided, doravirine dosing frequency should be increased from 100 mg once daily to 100 mg twice daily. A fixed-dose combination of doravirine with 3TC and TDF at the recommended adult doses of 100 mg doravirine and 300 mg each of 3TC and TDF is also available [9]. While the pharmacokinetic characteristics of doravirine support the administration of 100 mg doravirine with minimal restrictions due to intrinsic factors and DDIs, dose recommendations for the fixed-dose combination may be influenced by the effect of intrinsic factors, such as renal impairment, on the pharmacokinetic profiles of 3TC and/or TDF, which are primarily renally cleared [9]. The use of TDF has also been associated with the onset or worsening of renal impairment in some patients [9]. Additionally, drug interactions specific to 3TC or TDF may also result in recommendations of additional monitoring for AEs related to increases in concentration of the 3TC or TDF component, as in the case of co-administration of the fixed-dose combination with ledipasvir/sofosbuvir [9].

The collective data demonstrate that the overall DDI profile of doravirine allows the co-administration of doravirine with a diverse range of concomitant medications and may offer advantages over existing antiretroviral therapies. For example, several boosted PIs, including ritonavir-boosted atazanavir, ritonavir-boosted darunavir, and ritonavir-boosted lopinavir, are contraindicated with elbasvir/grazoprevir due to OATP1B1/3 inhibition leading to increased plasma grazoprevir concentrations [3]; efavirenz and etravirine/nevirapine are also contraindicated with elbasvir/grazoprevir due to the resulting decrease in elbasvir and grazoprevir exposures, and ritonavir-boosted tipranavir is expected to reduce ledipasvir and sofosbuvir concentrations [3]. Rilpivirine is contraindicated with proton-pump inhibitors, and raltegravir should not be co-administered with aluminum-/magnesium-containing hydroxide antacids [3]. Meanwhile, care must be taken when co-administering cobicistat-boosted elvitegravir with atorvastatin, and dolutegravir with metformin [3]. The broad suitability of doravirine in the presence of concomitant medications therefore offers freedom from some of the restrictions associated with other antiretroviral regimens and provides additional flexibility in managing polypharmacy. Similar conclusions have been drawn by other authors [106, 107].

As doravirine will be co-administered with other antiretroviral agents, the favorable drug-interaction profile supports the combination of doravirine with the most commonly used drugs, including 3TC and TDF [31]. These results contrast with the alterations in pharmacokinetics seen with other agents. For example, when TDF is co-administered with ritonavir-boosted atazanavir, decreased atazanavir exposure occurred [108]. Switching from a PI-, NNRTI-, or InSTI-based regimen to a doravirine-based regimen is also an important consideration. Phase III results supported a switch from commonly used regimens to doravirine [54], and thus doravirine has been approved to replace the current antiretroviral therapy in appropriate patients who are virologically suppressed on their current regimen [8, 9]. Based on drug interaction properties of other antiretroviral agents, this ease of switch may not be feasible for other drugs.

While it should be taken into consideration that data to date have been generated either under strictly controlled phase I trial conditions or in well-controlled phase II and phase III trials, which began to emulate real-world conditions but still included several restrictions for inclusion and exclusion, the safety, tolerability, and efficacy profile of doravirine is expected to evolve with its expanded use in clinical settings as a greater number of patients with co-morbidities and polypharmacy are treated with doravirine-based regimens. However, given the overall pharmacokinetic profile of doravirine and the benefits it brings compared with existing treatment options, it is expected that doravirine has the potential to become a valuable addition to the available treatments for HIV-1 infection across a diverse range of populations living with HIV.

Conclusions

In summary, evaluation of published clinical pharmacokinetics trials of doravirine demonstrates a low potential for DDIs with doravirine and limited impact of patient characteristics. Although doravirine is contraindicated for co-administration with strong CYP3A inducers and requires dose adjustment for co-administration with the moderate CYP3A inducer rifabutin, DDIs with other drugs are unlikely. As a result, its pharmacological profile makes doravirine a potential treatment option for a broad range of people living with HIV, including older populations and those with co-morbidities requiring the use of concomitant medications.

Electronic supplementary material

Acknowledgements

Author Contributions

MI, SK, SAS, and KLY designed the research. MI, SK, RS, SAS, LW. and KLY analyzed/interpreted the data. MI, SK, RS, SAS, LW, and KLY wrote or revised the manuscript.

Compliance with Ethical Standards

Footnotes

References