Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine
Alison Boyle1,2 · Catherine E. Moss2 · Catia Marzolini2,3 · Saye Khoo2

Springer Nature Switzerland AG 2019

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug–drug interactions and the resistance profile were assessed in this clini- cal review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15 h, median time to maximum plasma concentrations of 1–4 h, and time to steady-state concentration of 7 days. The pharmacokinetics of doravirine are not greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impair- ment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50 mL/min. Doravirine has a low potential for drug–drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100 mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the cur- rent armamentarium of drugs for the treatment of HIV infection.

 Saye Khoo [email protected]

1 Department of Pharmacy, NHS Greater Glasgow and Clyde, Glasgow, UK
2 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK
3 Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland

1 Introduction
Use of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and rilpivirine in preferred first-line regimens in human immunodeficiency virus (HIV) treat- ment guidelines has been increasingly replaced by inte- grase strand transfer inhibitors because of neuropsychiat- ric adverse events with efavirenz as well as an increasing prevalence of viral strains resistant to current NNRTIs [1–4]. Nevertheless, there is a need for an effective alter- native for individuals who cannot take integrase inhibitors. Doravirine is a novel HIV-1 NNRTI approved by the US Food and Drug Administration and European Medicines Agency in August and November 2018, respectively. It has favorable characteristics, equivalent efficacy [5–7] with an improved safety profile compared with efavirenz, enhanced in vitro activity against common NNRTI resistant muta- tions, and a low potential for drug–drug interactions. It is included in the US guidelines as an NNRTI option in the category of recommended initial regimens in certain clini- cal situations. It is available in two formulations: a single- agent film-coated tablet (Pifeltro®) containing 100 mg of doravirine and a single-tablet regimen in combination with nucleoside reverse transcriptase inhibitors (NRTIs) lami- vudine 300 mg and tenofovir disoproxil fumarate 300 mg (Delstrigo®).
This review outlines the clinical pharmacodynamics and pharmacokinetics of doravirine and provides an overview of key findings from clinical efficacy, safety, HIV resistance, and drug–drug interactions data. Suitable publications were identified by a PubMed search using the terms “doravirine” in combination with “pharmacokinetics”, “pharmacodynam- ics”, “drug interactions”, “pharmacology”, and “resistance”. Additionally, a snowballing strategy was used to collect other relevant studies.

2 Pharmacodynamics
2.1 Mechanism of Action

Doravirine is a novel pyridinone NNRTI that inhibits viral DNA synthesis by binding to a hydrophobic pocket close to the active site of the HIV-1 reverse transcriptase. Non- nucleoside reverse transcriptase inhibitor binding causes conformational changes within the reverse transcriptase active site, resulting in inhibition of the chemical step of polymerization [8, 9]. Doravirine does not inhibit the human cellular DNA polymerases α and ß and mitochon- drial DNA polymerase γ [10], reducing the risk of mito- chondrial toxicity.

2.2 Antiviral Activity

In vitro, doravirine has demonstrated potent antiviral activ- ity against wild-type HIV-1 virus (95% effective concentra- tion 20 nmol/L [8.5 ng/mL] in the presence of 50% normal human serum) [11]. Antiviral activity was also displayed against a range of different HIV-1 viral subtypes (A, B, C, D, F, G, H, J, and K) [11].
Two single- and multiple-ascending dose studies inves- tigated the pharmacokinetics of doravirine (6–1200 mg) in healthy male subjects. Single doses of doravirine, 12 mg and higher, resulted in a geometric mean trough plasma concen- tration (C24) exceeding the in vitro 95% inhibitory concen- tration (IC95) in 50% human serum of both wild-type virus (IC95 19 nM) and of common efavirenz resistance muta- tions, including K103N/Y181C (IC95 54 nM). These trough concentrations were sustained following multiple once-daily dosing. For the NNRTI class, there is a general association of efficacy with trough concentrations greater than the pro- tein-adjusted IC95 in the HIV spread assay. Therefore, these results were considered as one factor in the dose selection for the phase II dose-ranging study in HIV-infected patients [12].

2.3 Resistance

Doravirine has a unique resistance profile. It has demon- strated in vitro activity against wild-type HIV-1, as well as against common clinically relevant NNRTI resistance mutations, K103N, Y181C, and K103N/Y181C (95% effective concentration 43, 27, and 55 nmol/L (18.3, 11.5, and 23.4 ng/mL), respectively [11]), with the exception of V106A, Y188L, or F227L [13]. However, in vitro resistance studies suggest that mutant viruses selected with doravirine may remain susceptible to efavirenz and rilpivirine, and vice versa, allowing for the possibility of sequencing NNRTI use [14]. In particular, doravirine may have an important role for treatment-experienced patients with NNRTI resistance, or in countries experiencing an increasing prevalence of pre- treatment NNRTI resistance, including resource-limited countries [15].
In the phase III study comparing doravirine- and efa- virenz-based regimens (DRIVE-AHEAD, NCT02403674) [n = 364 in each group], the emergence of NNRTI resist- ance at virological failure of doravirine was low at 48 weeks [6]. Seven (1.9%) participants taking doravirine/lamivudine/ tenofovir disoproxil fumarate had mutations associated with doravirine resistance (including mutations at codons 106, 188, 221, 225, 227, and 318) with six of these conferring resistance to both doravirine and efavirenz. Five of the seven participants also developed genotypic resistance to

lamivudine. In the efavirenz group, 12 (3.3%) participants had mutations associated with efavirenz resistance, with two where phenotypic sensitivity to doravirine was not retained. Five of the 12 participants also developed genotypic resist- ance to lamivudine. In DRIVE-FORWARD (NCT02275780) [16], only one patient in the doravirine-based group (n = 383), who discontinued treatment early with a detect- able virus because of non-adherence, developed doravirine resistance with the V106L, H221Y, and F227C mutations.
The prevalence of doravirine resistance mutations (based on in vitro data) was assessed in both treatment-naive and NNRTI-experienced patients in two large European patient cohorts [17, 18]. Reassuringly, the prevalence of doravirine resistance-associated mutations was found to be very low (1.4%) in treatment-naïve patients (n = 9764), with the most prevalent mutations being V108I, Y188L, H221Y, and Y318F [19]. In those who had been previously treated with NNRTIs (n = 6893), intermediate-and high-level doravirine resistance was present in 12.7% and 6.1%, respectively [11]. The most common mutation was Y188L.
These studies provide evidence to suggest that the genetic barrier to NNRTI resistance is high with doravirine and it may be effective in the presence of baseline resistance. However, additional data are required to confirm these find- ings, and in vivo activity in patients with baseline resist- ance is awaited. There is currently a phase II open-label study evaluating the safety and efficacy of doravirine/lami- vudine/tenofovir disoproxil fumarate (100/300/245 mg) as a fixed-dose combination (FDC) tablet in treatment-naïve HIV-1-infected patients with NNRTI transmitted resistance (DRIVE-BEYOND, NCT02629822) [20]. This study is due
for completion around October 2020.

3 Clinical Efficacy and Safety
The safety and efficacy of doravirine have been investigated in three large phase III trials expected to be completed in 2021. The clinical efficacy and safety results of these studies are summarized in Table 1.
3.1 DRIVE‑FORWARD (NCT02275780)

DRIVE-FORWARD is a randomized, double-blind, non-inferiority phase III trial, which compares the effi- cacy of doravirine (100 mg daily) to darunavir/ritonavir (800/100 mg daily) with a dual NRTI backbone (either tenofovir disoproxil fumarate/emtricitabine [245/200 mg daily] or abacavir/lamivudine [600/300 mg daily]) in HIV- positive treatment-naïve adults [21]. After 48 weeks, dora- virine demonstrated no significant difference to darunavir/ ritonavir (non-inferior), with 83.8% (321/383) of patients

in the doravirine group achieving HIV RNA < 50 copies/ mL vs. 79.9% (306/383) in the darunavir/ritonavir group (mean difference 3.9%, 95% confidence interval [CI] − 1·6 to 9·4) [5]. The efficacy of doravirine is therefore similar to that seen in clinical trials for both efavirenz and rilpivirine [22, 23]. At week 48, mean CD4 cell count increased by 193 per µL in the doravirine group and 186 per µL in the darunavir/ritonavir group (mean difference 7.1 per µL, 95% CI − 20.8 to 35). Adverse events occurred at a similar rate in both groups; the most common side effect of both regimens was diarrhea. Additionally, patients in the doravirine group had a favorable fasting blood lipid profile, as compared with those in the darunavir/ritonavir group. Phenotypic resistance to doravirine did not develop in this study [5]. Longer term antiviral efficacy was maintained over 96 weeks (73.1% of patients receiving doravirine achieved HIV RNA < 50 copies/mL vs. 66.0% of those receiving darunavir/ritona- vir). Doravirine-treated patients continued to have a better lipid profile than those treated with darunavir/ritonavir and adverse-event rates were still similar in both groups [16].
3.2 DRIVE‑AHEAD (NCT02403674)

In a similarly designed trial, DRIVE-AHEAD, the efficacy of an FDC of doravirine, lamivudine, and tenofovir diso- proxil fumarate (100/300/300 mg daily) was compared with an FDC containing efavirenz/emtricitabine/tenofovir diso- proxil fumarate (600/200/300 mg daily) in treatment-naïve adults [24]. The primary efficacy and safety endpoints were the proportion of patients achieving plasma HIV RNA < 50 copies/mL at 48 weeks and the proportion of patients with neuropsychiatric adverse events in three pre-specified cat- egories (dizziness, sleep disorders, and altered sensorium), respectively. At 48 weeks, doravirine demonstrated non-infe- riority vs. efavirenz with 84.3% (307/364) of patients in the doravirine FDC group achieving HIV RNA < 50 copies/mL compared with 80.8% (294/364) in the efavirenz FDC group (difference 3.5%, 95% CI − 2.0 to 9.0). Adverse events were less frequent and neuropsychiatric adverse events were sig- nificantly lower in the doravirine FDC group compared with the efavirenz FDC group (dizziness [8.8% vs. 37.1%]; sleep disorders/disturbances [12.1% vs. 25.2%]; altered senso- rium [4.4% vs. 8.2%]). Mean CD4 cell count increased by 198 per µL in the doravirine FDC group and 188 per µL in the efavirenz FDC group compared with baseline. As in the DRIVE-FORWARD trial, doravirine was associated with a favorable lipid profile. Phenotypic resistance to doravirine developed in 1.6% (6/364) of participants in the doravirine group, while 3.0% (11/364) of patients developed resistance to efavirenz [6]. After 96 weeks, 77.5% of the doravirine FDC group achieved HIV RNA < 50 copies/mL, compared to 73.6% in the efavirenz FDC group (difference 3.8%,Immediate switch Switch after 24 weeks

HIV RNA < 50 copies/mL (24 weeks) 93.7% 94.6%
HIV RNA < 50 copies/mL (48 weeks) 90.8% 94.7%
Integrated safety analysis of DRIVE- FORWARD, DRIVE-AHEAD and
600/200/300 mg, daily) (800/100 mg, daily)
Discontinuation due to adverse event 2.5% 6.6% 3.1%
Neuropsychiatric disorders 25.0% 55.9% n/a
DF disoproxil fumarate, HIV human immunodeficiency virus, NNRTI non-nucleoside reverse transcriptase inhibitor
CI − 2.4 to 10.0). Favorable lipid profiles and adverse events rates continued in the doravirine FDC group and no addi- tional doravirine resistance was observed [25].
An integrated efficacy analysis of pooled 48-week data from both DRIVE-FORWARD and DRIVE-AHEAD reviewing 1494 study participants (747 doravirine, 383
darunavir/ritonavir, 364 efavirenz/emtricitabine/tenofovir disoproxil fumarate) provided further confirmation of the efficacy of doravirine 100 mg and doravirine/lamivudine/ tenofovir disoproxil fumarate FDC irrespective of baseline characteristics [6, 26]. Comparable antiviral activity was seen in all groups with 84.1%, 80.8%, and 79.9% of patients achieving HIV-1 RNA < 50 copies/mL with doravirine,

efavirenz/emtricitabine/tenofovir disoproxil fumarate, and darunavir/ritonavir, respectively. Premature discontinuation (without virological failure) was 10% in doravirine-based regimens, 20.1% with darunavir/ritonavir, and 16.7% with efavirenz. Low rates of virological failure were observed and were similar between the comparator groups. Treatment- emergent drug resistance in those who experienced virologi- cal failure was rare. Primary NNRTI and NRTI resistance were detected in seven (0.9%) and six (0.8%) patients receiv- ing doravirine, respectively, as compared with 12 (3.3%) and five (1.4%) patients receiving efavirenz. Primary NRTI or protease inhibitor resistance was not detected with daruna- vir-based regimens.

3.3 DRIVE‑SHIFT (NCT02397096)

DRIVE-SHIFT was a phase III, open-label non-inferiority trial comparing the safety and efficacy of switching to the doravirine/lamivudine/tenofovir disoproxil fumarate FDC from other antiretroviral therapy (specifically, boosted ataza- navir, darunavir, lopinavir, elvitegravir; or efavirenz, nevi- rapine, or rilpivirine, all in combination with two NRTIs) in patients with undetectable HIV-1 RNA [7]. Patients were randomized into two groups; immediate switch to doravirine FDC and delayed switch after continuation of current antiret- roviral therapy for 24 weeks. The primary endpoint was the percentage of patients achieving plasma HIV RNA < 50 copies/mL at 24 weeks after switching (24 weeks into the study for the immediate switch and 48 weeks for the delayed switch); the noninferiority margin was − 8%. At week 24, 93.7% (419/447) of the immediate-switch group achieved HIV RNA < 50 copies/mL as opposed to 94.6% (211/223) in the delayed-switch group (who remained taking their baseline antiretroviral therapy) [difference − 0.9%, 95% CI − 4.7 to 3.0]. At week 48, 90.8% (406/447) of the immediate-switch group had HIV RNA < 50 copies/mL (difference − 3.8%, 95% CI − 7.9 to 0.3). Of the 209 participants in the baseline regimen delayed-switch group who switched to doravirine FDC at week 24, 94.7% (198/209) achieved HIV RNA < 50 copies/mL at week 48. The lipid profiles of participants who had switched from ritonavir-boosted protease inhibitors were superior to those who remained taking ritonavir-boosted pro- tease inhibitors. Adverse events were higher in the immedi- ate-switch group, but most were mild [27].
A double-blind, randomized, dose-escalation study, in
which 18 treatment-naïve patients with HIV-1 received either doravirine 25 mg or 200 mg or matching placebo once daily for 7 days, reported similar reductions in viral load at both doses, with no viral breakthrough. This indi- cates the full antiretroviral effect of doravirine (as mono- therapy) has been achieved at each dose [19]. Safety and antiretroviral activity of four once-daily doses of doravirine (25 mg, 50 mg, 100 mg, and 200 mg) in combination with tenofovir disoproxil fumarate/emtricitabine was compared with efavirenz/tenofovir disoproxil fumarate/emtricitabine in another phase IIb, randomized, double-blind, dose-ranging study (NCT01632345) [28]. Of 210 patients randomized, 208 were treated (n = 40–43 per treatment group). Rates of virological suppression at week 24 were similar across all doses of doravirine, and efavirenz 600 mg once daily with fewer drug-related adverse events associated with dora- virine. Drug-related adverse events were reported in 35% of patients receiving doravirine (any dose n = 166) and by 57% of patients receiving efavirenz (n = 42). Serious adverse events were reported in 3% and 7%, respectively. Central nervous system adverse events did not appear to be dose related for doravirine. Central nervous system effects were

seen in 18%, 35%, 14%, and 15% in the 25-mg, 50-mg, 100- mg, and 200-mg doravirine groups vs. 33% in the efavirenz group. Following analysis, the 100-mg dose was selected for further study to allow for a safety margin in the context of potential drug–drug interactions as well as providing for- giveness for the occasional missed dose.
An integrated safety analysis of the phase III trials (DRIVE-FORWARD; DRIVE-AHEAD) and phase IIb
(P007) [NCT01632345] demonstrated that doravirine has a favorable safety profile compared with darunavir/ritona- vir or efavirenz and improved tolerability profile compared with efavirenz [29]. The occurrence of drug-related adverse events was similar for doravirine (30.9%) and darunavir/ ritonavir (32.1%) but higher for efavirenz-based regimens (61.4%). The proportion of patients discontinuing doravirine therapy because of an adverse event was lower than efavirenz (2.5% vs. 6.6%, respectively) and similar to darunavir/ritona- vir (2.5% vs. 3.1%) in the main safety population (n = 1710). In a smaller special safety population (n = 944; 472 patients in each doravirine and efavirenz treatment groups), a statisti- cally significantly lower percentage of patients discontinued doravirine because of adverse events compared with efa- virenz (2.8% vs. 6.1%, respectively, p = 0.012). In the same population, neuropsychiatric disorders were less common in the doravirine group (25.0%) compared with the efavirenz group (55.9%). A more favorable low-density lipoprotein- cholesterol and non-high-density lipoprotein-cholesterol profile, but a smaller increase in high-density lipoprotein- cholesterol, was observed with doravirine compared with darunavir/ritonavir and efavirenz. The most common adverse events occurring with doravirine were headache (13.3%), diarrhea (12.4%), nasopharyngitis (9.5%), nausea (9.5%), and dizziness (7.1%). At a supratherapeutic dose of 1200 mg, which provides approximately four times the peak concentration observed following the recommended dose, doravirine did not prolong the QTc interval to any clinically relevant extent [30].
3.4 Other Comparators

There are no currently available data to compare the effi- cacy, safety, and tolerability of doravirine to integrase strand transfer inhibitors that are currently included in the first-line regimens in many international HIV treatment guidelines.

4 Clinical Pharmacokinetics
4.1 Absorption

Doravirine is rapidly absorbed with a median time to maxi- mum plasma concentration of 1–4 h after oral administration. The target trough concentration (C24) for doravirine is not

known. During drug development, a putative target for dose selection was a C24 of 23 ng/mL (54 nM), a plasma concentra- tion based on an in vitro estimate of 95% efficacy in the pres- ence of 50% normal human serum against the NNRTI K103N/ Y181C double substitution [31]. With a dose of doravirine 100 mg daily, steady-state concentrations are achieved after 7 days of dosing [12], with a geometric mean maximal con- centration (Cmax) of 962 ng/mL (coefficient of variation: 19%), area under the plasma concentration-time curve from time 0 to 24 h (AUC0–24) of 16,090 ng × h/mL, and C24 of 396 ng/ mL [10]. The bioavailability is 64% after administration of a 100-mg tablet [10] and is not affected to any significant extent when doravirine is taken with food [32]. In vitro data have demonstrated that doravirine is a substrate of P-glycoprotein (P-gp) [33], but owing to high passive permeability, interac- tions with P-gp inhibitors are not anticipated to be clinically relevant [34] with single-dose rifampin (P-gp inhibitor [35]) having minimal impact on doravirine exposure [36].
4.2 Distribution

Doravirine exhibits moderate protein binding of around 75%
[12] and has a volume of distribution of 60.5 L after intrave- nous administration indicating distribution into tissues [37].
4.3 Metabolism

In vitro studies indicate that doravirine is a substrate of both CYP3A4 and CYP3A5, with metabolism by CYP3A4 demon- strating a 20-fold higher efficiency as compared with CYP3A5 [38]. Although CYP3A oxidation is the primary mechanism of elimination of doravirine, the intrinsic clearance of doravirine is low [37]. A study with radiolabeled doravirine showed that the main oxidative metabolite of doravirine (designated M9) accounted for 12.9% of circulating radioactivity (Fig. 1). Two other metabolites were present in the plasma; however, to a lim- ited extent—a glucuronide of M9 and an N-acetyl-cysteine con- jugate of doravirine. Doravirine does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 nor does it induce CYP1A2, 2B6, or 3A4 messenger RNA expression at relevant concen- trations in vitro. Furthermore, doravirine does not inhibit the glucuronidation enzyme UGT1A1. In vitro data have also indi- cated that doravirine has a low potential to interfere with the transport of drugs because it does not inhibit OATPB1/3, BSEP, BCRP, OAT1/3, OCT2, MATE1/2K, or P-gp at clinically rel- evant doses. Doravirine is not transported by OATPB1/3 but enters the hepatocytes via passive diffusion [34].

4.4 Elimination

Doravirine is eliminated primarily by oxidative metabolism as described above. Excretion of unchanged drug in urine

or in bile is thought to be minor. In one study, only ~ 6% of unchanged doravirine was found in the urine over a 24-h period, and renal clearance was low at 9.43 mL/min [12]. In another study, 39% of the absorbed dose of doravirine was recovered as M9 in the urine and 16% as M9 in the feces. These results indicate that while biliary excretion could con- tribute, renal excretion is the primary route for clearance of M9 [37]. The terminal half-life (t1/2) for doravirine is ~ 15 h, supporting once daily dosing [10].
5 Pharmacokinetics in Special Populations
5.1 Renal Impairment

As renal excretion of unchanged doravirine is limited, no impact of mild or moderate renal impairment is expected. A single dose of doravirine 100 mg was given to eight patients with severe renal impairment (estimated glomerular filtra- tion rate < 30 mL/min/1.73 m2) and eight healthy controls (estimated glomerular filtration rate ≥ 80 mL/min/1.73 m2). Doravirine area under the curve and C24 values increased by 43% (geometric mean ratio, GMR [90% CI], 1.43 [1.0–20.4])
and 38% (1.38 [0.99–1.92]), respectively. Apparent terminal
t1/2 was 25 h in subjects with severe renal impairment vs.
16.7 h in those without. Elimination of doravirine may be slowed, potentially resulting in a modest increase in over- all exposure. These changes are not considered clinically relevant and are well within tolerable limits. Thus, no dose adjustment is required in mild, moderate, or severe renal impairment [39]. However, the FDC tablet, with lamivudine and tenofovir disoproxil fumarate, is not recommended if creatinine clearance is < 50 mL/min (as dosages of lami- vudine/tenofovir disoproxil fumarate cannot be adjusted as required) [10]. Additionally, doravirine/lamivudine/tenofo- vir disoproxil fumarate should be avoided with concomitant or recent use of nephrotoxic drugs because of the risk of renal impairment with tenofovir [10]. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.
5.2 Hepatic Impairment

A single dose of doravirine was administered to eight healthy subjects, and eight individuals with a Child-Pugh score of 7–9 (moderate hepatic impairment). No clinically significant difference in the pharmacokinetics of dora- virine was observed in subjects with moderate hepatic impairment compared to subjects without hepatic impair- ment. The observed GMR [90% CI; moderate hepatic impairment/healthy subjects] was 0.90 [0.66–1.24] for
Cmax, 0.99 [0.74–1.33] for C24, 0.99 [0.72–1.35] for area

Fig. 1 Metabolism of doravirine to the main metabolite M9 [37]. CYP cytochrome P450

under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0–inf), and 0.93 [0.74–1.18] for AUC0–24. The lack of effect on doravirine exposure may be explained by its low intrinsic metabolic clearance. No dose adjustments are necessary for patients with mild- moderate hepatic impairment [40]; however, caution is needed when prescribing in patients with severe hepatic impairment (Child-Pugh score C) as no data are available on doravirine exposure in this clinical situation [10].

5.3 Pregnancy and Lactation

There are limited data on the use of doravirine in pregnant women and use in pregnancy should be avoided where pos- sible. Embryo-fetal developmental studies conducted in rats found no adverse effects on maternal health or embryo-fetal development up to a maximum feasible dose of 450 mg/ kg/day [31, 34]. Thus, the no-observed-adverse-effect- level for maternal toxicity and embryo-fetal development

was 450 mg/kg/day (AUC 0–24: 146,884 ng × h/mL), approximately nine-fold above the clinical area under the curve exposure. In rabbits, maternal toxicity (based on body weight loss) was observed in embryo-fetal development studies at the maximum feasible dose of 300 mg/kg. Thus, the no-observed-adverse-effect-level for F0 maternal toxicity was 15 mg/kg/day, providing an exposure of 34,486 ng × h/ mL, which is approximately 2.1-fold above the clinical area under the curve exposure at the 100-mg daily dose. Fetal abnormalities (multiple external and skull malformations) were observed during assessment of developmental toxicity in the F1 generation. However, these abnormalities were not considered to be related to doravirine treatment as the con- cerning findings occurred within a historical control range, were single occurrences and demonstrated no dose–response relationship [31]. This finding was not observed in the rat toxicology studies. It is unknown if doravirine is excreted into human breast milk. However, animal pharmacodynamic studies have shown that doravirine is excreted into the milk

of lactating rats at concentrations approximately 1.5 times that of maternal plasma concentrations [10, 34].
5.4 Population Pharmacokinetics

There was a modest effect of age and body weight on dora- virine exposure and C24 (less than 25% change in pharma- cokinetic parameter values) in a typical population with HIV-1 [41]. These changes were not considered clinically meaningful. Other covariates, such as race, ethnicity, sex, and body mass index, had no significant impact on dora- virine exposure or C24 (ranging from a 34% decrease to a 69% increase). The covariate effects estimated in the popu- lation-pharmacokinetic analysis were comparable to those observed in the phase I, healthy volunteer study evaluating the impact of age and sex on doravirine pharmacokinetics [42]. No dose adjustments are required for any of the covari- ates studied [10].

6 Drug–Drug Interactions
As previously described, doravirine has a low potential for drug–drug interactions. It does not affect cytochrome P450 (CYP) pathways, UGT1A1 enzyme, or transporter proteins in vitro. However, CYP3A plays an important role in the metabolism of doravirine and inhibitors or inducers of this enzyme may have an impact on doravirine exposure. Results from clinical pharmacokinetic studies performed to evaluate drug–drug interactions between doravirine and other drugs are summarized in Figs. 2 and 3. A comprehensive database of drug–drug interactions involving doravirine can be found on the Liverpool drug interactions website http://www.hiv- druginteractions.org.
6.1 Impact of Co‑Medications on Doravirine Pharmacokinetics

Doravirine exposure substantially increases in the pres- ence of the CYP3A inhibitors ritonavir and ketoconazole [43]. Co-administration of doravirine with multiple doses of CYP3A4 inhibitors, ritonavir and ketoconazole, was assessed in two open-label, phase I cross-over studies in healthy volunteers [43]. Co-administration with both ritona- vir and ketoconazole increased doravirine AUC0–inf and C24 by approximately threefold, with a lesser impact observed on Cmax (30% increase with ritonavir and 25% increase with ketoconazole). Co-administration was generally well toler- ated, with only mild or moderate adverse effects reported and no clinically relevant changes in laboratory tests, vital signs, or electrocardiograms observed. Clinical experience of doravirine across drug development trials at higher expo- sures (up to 6.4-fold increases) suggests that the observed

increases with CYP3A inhibitors are not likely to be clini- cally meaningful [12]. As a result, strong CYP3A inhibitors were permitted in phase III trials with doravirine and, in practice, can be co-administered without the need for dose adjustment [10].
Conversely, CYP3A inducers have been shown to reduce doravirine exposure. The impact of both single and multi- ple doses of rifampin on doravirine exposure was evaluated [36]. Rifampin inhibits intestinal P-gp after a single oral dose (with co-administration in close temporal proximity) and hepatic OATP1B1/B3. However, on long-term admin- istration, potent induction of CYP3A, P-gp, and OATP1B1 predominates. Doravirine AUC0–inf and C24 were relatively unchanged in the presence of single-dose rifampin although an increase in Cmax was observed, GMR (90% CI): 1.40 (1.21–1.63). This small increase may be explained by weak P-gp inhibition at the gut wall limited by high permeability of doravirine. However, significant reductions in doravirine pharmacokinetic parameters were observed when co-admin- istered with multiple-dose rifampin, consistent with a strong induction of CYP3A [36, 44]. Geometric mean ratios (90% CIs) [doravirine plus multiple-dose rifampin vs. doravirine alone] for doravirine AUC0–inf, C24, and Cmax were 0.12 (0.10–0.15), 0.03 (0.02–0.04), and 0.43 (0.35–0.52), respec-
tively (Fig. 2). The geometric mean apparent clearance of
doravirine was increased eightfold and the geometric mean apparent terminal t1/2 was reduced from 18.6 to 6.3 h. The significant reduction in doravirine pharmacokinetics with multiple doses of rifampin is likely to reduce the efficacy of doravirine to below in vitro and in vivo efficacy targets. As a result, rifampin, along with other potent CYP3A enzyme inducers such as carbamazepine, phenytoin, and St John’s Wort, is contraindicated with doravirine [10].
Rifabutin is a moderate CYP3A inducer and is frequently used as an alternative to rifampin for tuberculosis in situa- tions where drug–drug interactions are present, particularly in HIV co-infected patients. Co-administration of single- dose doravirine 100 mg with steady-state rifabutin resulted in a reduction in AUC0–inf and C24 by approximately 50% and 68%, respectively. Maximum plasma concentration remained comparable to doravirine single dose alone [44]. Geometric mean ratios (90% CIs) [doravirine plus rifabu- tin vs. doravirine alone] for AUC0–inf, C24, and Cmax were 0.50 (0.45–0.55), 0.32 (0.28–0.35), and 0.99 (0.85–1.15),
respectively (Fig. 2). The lack of effect on doravirine Cmax reinforces previous observations that P-gp does not play a significant role in limiting the absorption of doravirine. Apparent clearance was significantly increased from 5.9 to
12.2 L/h and apparent terminal t1/2 was shortened from 15.7 to 9.4 h with co-administration. Nonparametric superposi- tion analysis was used to evaluate whether increasing dora- virine to 100 mg twice daily would overcome the reductions observed with 100 mg once daily when co-administered
Drug interaction
Tenofovir 300 mg daily
+ DOR 100 mg single dose(1)

Dolutegravir 50 mg daily + DOR 200 mg daily(2)

No dosage adjustment

No dosage adjustment

EFV 600 mg daily (14 days), followed by DOR

No dosage adjustment when switching from EFV to DOR in a virologically
100 mg daily (14 days)(3) post EFV
supressed population
Ritonavir 100 mg BID
+ DOR 50 mg single dose

(4)No dosage adjustment

Ketoconazole 400 mg daily
+ DOR 100 mg single dose(5)
Rifampicin 600 mg daily (13 doses)
+ DOR 100 mg single dose(6)

Rifabutin 300 mg daily (14 doses)
+ DOR 100 mg daily(7)
Oral antacid suspension*
+ DOR 100 mg single dose(8)

Pantoprazole 40 mg (oral) daily
+ DOR 100 mg single dose(8)
Methadone 20-180 mg daily
+ DOR 100 mg daily(9)
Elbasvir/grazoprevir 50/100 mg daily
+ DOR 100 mg QD(10)
Ledipasvir/sofosbuvir 90/400 mg daily + DOR 100 mg single dose(11)

No dosage adjustmentSignificant reduction in DOR levels. Co- administration is contraindicatedIncrease DOR to 100mg BID and for at least 2 weeks after rifabutin cessationdosage adjustmentNo dosage adjustment No dosage adjustmentNo dosage adjustment0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 2.75 3 3.25 3.5 3.75 4 4.25 4.5

Change relative to doravirine administered alone*Aluminium hydroxide 1600 mg, Magnesium hydroxide 1600 mg and simethicone 160mg
Fig. 2 Impact of co-medications on doravirine (DOR) pharmacoki- netics from phase I cross-over studies in healthy volunteers. Data are presented as area under the curve (squares) and trough plasma concentration (triangles) geometric mean ratios ± 90% confidence intervals for DOR when administered with or without co-medica- tions. BID twice daily, EFV efavirenz. (1) Period 1, single-dose DOR 100 mg followed by 7-day washout. Period 2, tenofovir disoproxil fumarate 300 mg daily for 18 days, with single-dose DOR 100 mg on day 14 (n = 8) [34]. (2) Period 1, dolutegravir 50 mg daily for 7 days.
Period 2, DOR 200 mg daily for 7 days. Period 3, DOR 200 mg daily
with dolutegravir 50 mg daily for 7 days (n = 12) [49, 51]. (3) Period 1, DOR 100 mg daily for 5 days followed by 7-day washout. Period 2, efavirenz 600 mg daily for 14 days. Period 3, DOR 100 mg daily for 14 days (n = 20) [45]. (4) Period 1, single-dose DOR 50 mg followed by 7-day washout. Period 2, ritonavir 100 mg BID for 20 days, with single-dose DOR 50 mg on day 14 (n = 8) [52]. (5) Period 1, single- dose DOR 100 mg followed by 7-day washout. Period 2, ketocona- zole 400 mg daily for 10 days, with single-dose DOR 100 mg on day 2 (n = 10) [53]. (6) Period 1, single-dose DOR 100 mg followed by 7-day washout. Period 2, rifampin 600 mg with single-dose DOR

100 mg on day 1, followed by rifampin days 4–18 with DOR 100 mg co-administered on day 17 (n = 10) [36, 53]. (7) Period 1, single-dose DOR 100 mg followed by 7-day washout. Period 2, rifabutin 300 mg daily on days 1–16 with single-dose DOR 100 mg on day 14 (n = 18) [44]. (8) Period 1, single-dose DOR 100 mg. Period 2, single-dose antacid oral suspension (aluminium hydroxide [1600 mg], magne- sium hydroxide [1600 mg], and simethicone [160 mg] single-dose DOR 100 mg. Period 3, pantoprazole 40 mg daily on days 1–5 with single-dose DOR 100 mg on day 5. A washout of 10 days between periods was observed (n = 14) [46]. (9) Methadone 20–180 mg daily
for days 1–7 with DOR 100 mg daily on days 2–6 (n = 14) [34]. (10) Period 1, DOR 100 mg daily for 5 days, followed by 5-day washout. Period 2, elbasvir/grazoprevir (50/200 mg) daily for 10 days. Period 3, DOR 100 mg, elbasvir/grazoprevir (50 mg/200 mg) co-adminis- tered for 5 days (n = 12) [50]. (11) 3-Period crossover study. On day 1, subjects received single-dose DOR 100 mg, single-dose ledipasvir 90 mg/sofosbuvir 400 mg (LED/SOF), or co-administered DOR plus LED/SOF. Subjects received each treatment on one occasion with 14-day washout between doses (n = 14) [50]with rifabutin. Similar C24 values were predicted with this combination and area under the curve and Cmax were within 15% of those associated with doravirine 100 mg daily administered alone. These changes were not considered clinically meaningful and it is recommended that doravirine be prescribed at a dose of 100 mg twice daily when used in combination with rifabutin and this dose should be contin- ued for at least 2 weeks after cessation of rifabutin owing to the persisting inducing effect upon discontinuation of an inducer. There are no published data with other moder- ate CYP3A inducers, such as bosentan or modafinil, and co-administration of these drugs should be avoided if pos- sible [10]. For further advice on management of predicted drug–drug interactions, see http://www.hiv-druginteraction s.org.

Efavirenz is an NNRTI that has moderate CYP3A4 induc- tion potential. For those experiencing adverse effects relat- ing to efavirenz, including central nervous system-related

(6)Elbasvir/grazoprevir 50/100 mg daily + DOR 100 mg daily(7)Ledipasvir/sofosbuvir 90/400 mg daily + DOR 100 mg single dose(8)Change relative to drug administered alone
Fig. 3 Impact of doravirine (DOR) on the pharmacokinetics of co- medications from phase I cross-over studies in healthy volunteers. Data are presented as area under the curve (squares) and trough plasma concentration (triangles) geometric mean ratios ± 90% con- fidence intervals for co-medication when administered with or with- out DOR. EE ethinylestradiol, LNG levonorgestrel. (1) Period 1, dolutegravir 50 mg daily for 7 days. Period 2, DOR 200 mg daily
for 7 days. Period 3, DOR 200 mg daily with dolutegravir 50 mg
daily for 7 days (n = 12) [49, 51]. (2) DOR 120 mg daily for 14 days with a single dose of oral midazolam 2 mg on day 12 (n = 10) [12].
(3) Period 1, single-dose EE/LNG 0.03 mg/0.15 mg followed by 7-day washout. Period 2, DOR 100 mg daily for 17 days with EE/ LNG 0.03 mg/0.15 mg on day 14 (n = 19) [54]. (4) Period 1, single- dose atorvastatin 20 mg. Period 2, DOR 100 mg daily for 8 days with single-dose atorvastatin 20 mg on day 5 (n = 16) [48]. (5) Period 1, single-dose metformin 1000 mg followed by 3-day washout. Period 2, DOR 100 mg daily for 7 days with single-dose metformin 1000 mg
on day 5 (n = 15) [34]. (6) Methadone 20–180 mg daily for days
1–7 with DOR 100 mg daily on days 2–6 (n = 14) [34]. (7) Period 1, DOR 100 mg daily for 5 days, followed by 5-day washout. Period 2, elbasvir/grazoprevir (50/200 mg) daily for 10 days. Period 3, DOR 100 mg, elbasvir/grazoprevir (50 mg/200 mg) co-administered for 5 days (n = 12) [50]. (8) 3-Period crossover study. On day 1, subjects received single-dose DOR 100 mg, single-dose ledipasvir 90 mg/ sofosbuvir 400 mg (LED/SOF), or co-administered DOR plus LED/ SOF. Subjects received each treatment on one occasion with 14-day washout between doses (n = 14) [50]toxicities, doravirine may be an appropriate therapeutic alternative. As the induction effects of efavirenz persist for some time after the cessation of therapy, the impact on dora- virine pharmacokinetics after efavirenz switch was assessed in a drug–drug interaction study [45]. Efavirenz 600 mg once daily was administered for 14 days followed by doravirine 100 mg once daily for 14 days. On day 1 after efavirenz ces- sation, doravirine AUC0–24, Cmax, and C24 were reduced by 62%, 35%, and 85%, respectively, compared with doravirine alone. By day 14, the impact on doravirine pharmacokinetic

parameters persisted but reductions were less pronounced (AUC0–24, Cmax, and C24 reduced by 32%, 14%, and 50%, respectively). A slow decline in efavirenz concentrations was observed owing to its long half-life (40–55 h). The authors concluded that the temporary reduction in doravirine expo- sure in the presence of gradually reducing efavirenz concen- trations is unlikely to impact on viral suppression to a clini- cally significant extent. No dose adjustment of doravirine is recommended. The clinical relevance of this interaction has also been investigated in the phase III trial, DRIVE-SHIFT,

which has demonstrated non-inferior efficacy and acceptable safety in virally suppressed patients switching from various HIV therapies, including efavirenz-based regimens to dora- virine/lamivudine/tenofovir disoproxil fumarate at 48 weeks [27].
Unlike some other antiretrovirals, doravirine is not antic- ipated to interact with acid-reducing agents and cation- containing antacids owing to its pH-independent solubility. This was confirmed by a study evaluating the impact of an oral antacid suspension (containing aluminum hydroxide, magnesium hydroxide, simethicone) and pantoprazole on single-dose doravirine pharmacokinetics [46, 47]. No change in doravirine AUC0–inf and C24 was observed with co-administration of the oral antacid suspension. Slightly reduced Cmax values were observed (GMR [90% CI]: 0.86 [0.74–1.01]) for doravirine plus antacid suspension vs. dora- virine alone, which was not considered to be significant. Very small changes in AUC0–inf, Cmax, and C24 were seen when pantoprazole was co-administered with doravirine. However, these changes were not considered to be clini- cally meaningful. The impact of other co-medications on doravirine exposure and C24 is depicted in Fig. 2.
6.2 Impact of Doravirine on the Pharmacokinetics of Co‑Medications

Drug–drug interactions trials have shown that doravirine does not have a clinically meaningful effect on the phar- macokinetics of midazolam [12], atorvastatin [48], oral contraceptives, metformin, tenofovir, dolutegravir [49], and methadone (Fig. 3), supporting in vitro findings that it is unlikely to impact on the pharmacokinetics of other drugs via drug-metabolizing enzymes or transporter pathways [34]. In addition, there was no clinically significant effect on elbasvir/grazoprevir or ledipasvir/sofosbuvir exposure when co-administered with doravirine [50]. Modest, but not clinically meaningful, increases in doravirine phar- macokinetic parameters were observed with elbasvir/gra- zoprevir (AUC0–24, Cmax, and C24 increased by 56%, 48%, and 61%, respectively). Geometric mean ratios (90% CI) of doravirine AUC0–24, Cmax, and C24 for the doravirine plus elbasvir/grazoprevir vs. doravirine alone comparison were 1.56 (1.45–1.68), 1.41 (1.25–1.58), and 1.61 (1.45–1.79),
respectively. Ledipasvir/sofosbuvir co-administration had minimal impact on doravirine pharmacokinetics. Thus, these commonly prescribed hepatitis C virus direct-acting antiviral regimens may be co-administered with doravirine for hepatitis C virus/HIV co-infection with no dose adjust- ment. The impact of doravirine on other co-medications is depicted in Fig. 3. Overall, pharmacokinetic studies have corroborated that doravirine has an extremely low potential for clinically significant drug–drug interactions and this is

of particular benefit when evaluating its place in clinical practice guidelines for the treatment of HIV.

7 Conclusions
Doravirine has been shown to be a highly efficacious and well tolerated addition to the current therapeutic options for the treatment of HIV. A unique resistance profile and very low potential for drug–drug interactions have contributed to its inclusion in international treatment guidelines. Further clinical trial data are awaited to confirm efficacy in patients with transmitted NNRTI resistance and, if positive, will pro- vide a vital new treatment option for areas where NNRTI resistance is highly prevalent. Wider deployment of dora- virine will ultimately depend on its affordability and avail- ability particularly for low- and middle-income countries, set against alternatives such as efavirenz and dolutegravir. The prevalence of specific primary transmitted mutations confer- ring resistance to non-nucleosides may also be a considera- tion. It is also worth noting that doravirine could become a preferred alternative for those intolerant to dolutegravir- or efavirenz-based regimens.
Compliance with Ethical Standards

Funding No sources of funding were received for the preparation of this article.

Conflict of interest Alison Boyle has received honoraria for lectures from Gilead. Catherine E. Moss has no conflicts of interest that are directly relevant to the content of this article. Catia Marzolini has re- ceived research funding from Gilead and honoraria for lectures from MSD. Saye Khoo has received support from ViiV Healthcare, Gilead Sciences, Merck, and Janssen for research, and for the Liverpool Drug Interactions resource.


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