wild type reverse transcriptase(IC50= 4.5 nM);K103N reverse transcriptase(IC50= 5.5 nM);Y181C reverse transcriptase(IC50= 6.1 nM)
Doravirine (CAS#: 1338225-97-0) targets HIV-1 reverse transcriptase (RT). Biochemical IC50: wild-type (WT) RT = 4.5 ± 0.8 nM; K103N RT = 5.5 ± 0.8 nM; Y181C RT = 6.1 ± 1.3 nM. [1]
Cellular antiviral activity (EC95) in the presence of 50% normal human serum: WT = 20 ± 6.7 nM; K103N = 42 ± 7.8 nM; Y181C = 27 ± 14 nM; K103N/Y181C = 55 ± 14 nM. [1]
EC95 against WT virus in 10% serum = 11.0 ± 2.6 nM. [1]

Doravirine is a highly specific nonnucleoside reverse transcriptase inhibitor with very little off-target activity, according to studies on selectivity and cytotoxicity. Doravirine exhibits remarkable efficacy in inhibiting the replication of WT virus, with a 95% effective concentration (EC95) of 20 nM, and mutant viruses K103N, Y181C, and K103N/Y181C, with EC9595 of 43, 27, and 55 nM, respectively, when 50% normal human serum (NHS) is present. Comparable antiviral effects of doravirine have been observed against 93 viruses, representing 10 distinct HIV-1 subtype viruses[1].

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Doravirine (CAS#: 1338225-97-0) is a highly specific NNRTI with minimum off-target activities. It shows no cytotoxicity up to 100 μM in resting/activated CD4+ T cells, PBMCs, monocytes, macrophages, and proliferating cell lines (MT4, SupT1, HL60). [1]
It inhibits human DNA polymerases α, β, and γ with IC50 >100 μM (>10,000-fold selectivity vs HIV-1 RT). [1]
In a panel of >110 protein targets (enzymes, transporters, ion channels, receptors), doravirine (CAS#: 1338225-97-0) showed IC50 >10 μM against all except 5-HT2B (ligand binding IC50 = 2.5 μM), but no functional 5-HT2B response was observed. [1]
Antiviral activity against 10 different HIV-1 subtypes (A, B, C, D, F, G, H, J, K; total 93 viruses) showed fold change ≤1.5 vs control. [1]
Against a panel of 96 NNRTI-associated clinical mutant viruses, doravirine (CAS#: 1338225-97-0) had a superior resistance profile to efavirenz and comparable to etravirine and rilpivirine. Only 2 out of 23 mutants (Y188L and V106A/G190A/F227L) showed >50-fold reduced susceptibility. [1]
E138K and K101E mutants (associated with rilpivirine) were susceptible to doravirine with fold change <3. [1]
In two-drug combination studies with 18 FDA-approved antiretroviral agents, doravirine (CAS#: 1338225-97-0) showed non-antagonistic (additive) effects; slight synergy was observed with raltegravir (synergy volume 60.8 μM²%). [1]

When 50 mg of doravirine is administered along with a high-fat meal, there is no change in Cmax but there are modest increases in AUC time zero to infinity and C24 h[2].
In healthy male subjects, single oral doses of doravirine (CAS#: 1338225-97-0) from 6 to 1200 mg were generally well tolerated. Multiple once-daily doses from 30 to 750 mg for up to 10 days were also well tolerated. Trough concentrations (C24h) exceeding the in vitro IC95 (19 nM) were achieved with single doses ≥12 mg and maintained with once-daily dosing. [2]
Administration of 50 mg with a high-fat meal slightly increased AUC0-∞ (GMR 1.33) and C24h (GMR 1.56) with no change in Cmax (GMR 0.95). [2]
Co-administration of doravirine (CAS#: 1338225-97-0) 120 mg once daily at steady state with a single 2 mg dose of midazolam (CYP3A4 substrate) reduced midazolam AUC0-∞ by 18% (GMR 0.82, 90% CI 0.70-0.97), with no change in Cmax (GMR 1.02). [2]

HIV-1 reverse transcriptase biochemical assay: Full-length WT or mutant RT proteins (50 pM) were preincubated with inhibitor or DMSO in assay buffer (62.5 mM Tris-HCl pH 7.8, 1.25 mM DTT, 7.5 mM MgCl2, 100 mM KCl, 0.03% CHAPS, 0.125 mM EGTA) for 30 min at room temperature. Reaction initiated by adding template/primer (biotinylated DNA primer annealed to 500-nt RNA template, final 16.6 nM) and dNTPs (2 μM dCTP, dGTP, dATP; 66.6 nM Ru-dUTP). After 90 min at 37°C, reaction quenched with 25 mM EDTA, transferred to avidin plates, and product quantified by electrochemiluminescence. [1]

Cell-based multiple-cycle replication assay: MT-4 human T-lymphoid cells infected with HIV-1 isolate R8 (WT or mutant) at low MOI in medium containing 10% or 50% normal human serum. Compounds added in serial dilutions. After 3 days, p24 antigen in supernatant quantified by AlphaLISA. EC95 values determined. [1]
Single-cycle replication assay (PhenoScreen) for subtype and mutant viruses: performed by Monogram Biosciences using a variation of their clinical diagnostic assay. [1]
Cytotoxicity assay: Cells (resting/activated CD4+ T cells, PBMCs, monocytes, macrophages, MT4, SupT1, HL60) plated in 96-well plates, treated with 12-point serial dilutions of doravirine (CAS#: 1338225-97-0) (up to 100 μM) for 72 h, then alamarBlue added and fluorescence measured. [1]
Human DNA polymerase assay: Reactions contained 0.05 mg/mL gapped fish sperm DNA, 1.6 μM each dNTP with 3 μCi [³³P]dATP, and polymerase (α, β, or γ). Inhibitor concentrations 1-100 μM. Reactions initiated by adding polymerase, incubated 30 min (60 min for γ), quenched with 0.5 M EDTA, spotted on filter disks, washed, and counted. [1]
Two-drug combination study: CEM-SS or MAGI-CCR5 cells infected with HIV-1 (IIIB or Ba-L) and treated with doravirine (CAS#: 1338225-97-0) plus each of 18 FDA-approved antiretrovirals. Data analyzed using MacSynergy II three-dimensional model. [1]

Two Phase I double-blind, randomized, placebo-controlled studies in healthy male subjects (study 1: n=50, ages 20-49; study 2: n=16, ages 23-50). [2]
Single-dose (study 1): Doses 6, 12, 25, 50, 100, 150, 300, 450 mg (fasted); 50 mg (fed). 7-14 day washout. [2]
Single-dose (study 2): Doses 600, 800, 1000, 1200 mg (fasted). [2]
Multiple-dose (study 1): Doses 30, 60, 120, 240 mg once daily for 10 days (120 mg for 14 days with midazolam). [2]
Multiple-dose (study 2): Doses 500 and 750 mg once daily for 10 days. [2]
Doravirine tablets (1, 10, 100 mg potency) or matching placebo administered orally. Blood samples collected at multiple time points for PK analysis. Midazolam 2 mg syrup given on days -1 and 13 (study 1, 120 mg panel). [2]

Absorption, Distribution and Excretion
The absolute bioavailability of doravirine is 64%, with a time to peak concentration (Tmax) of 2 hours. All administered doses of [14C]doravirine are recovered after oral administration, indicating good absorption. Furthermore, clinical studies have shown that co-administration with food does not significantly alter the pharmacokinetic characteristics of doravirine. The primary elimination pathway of doravirine is via metabolism by cytochrome P450 3A4/5. Only 6% of the administered dose is excreted unchanged in the urine, with even less in the feces. The steady-state volume of distribution after intravenous doravirine administration is 60.5 L. The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively. Metabolisms/Metabolites After absorption, the unchanged drug is the main circulating component in plasma. Its M9 metabolite—a cytochrome P450 3A4/5-mediated oxidative metabolite—is the most abundant circulating doravirine metabolite.

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Biological Half-Life
The elimination half-life of doravirine is 15 hours.

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Doravirine (CAS#: 1338225-97-0) is rapidly absorbed with median Tmax 1-5 h post-dose. Apparent terminal half-life 12-21 h. AUC and Cmax increase slightly less than dose-proportionally. Steady state achieved by day 7. Accumulation ratios (day10/day1) for AUC0-24h, Cmax, and C24h were 1.1-1.5. [2]
Mean effective accumulation half-life ~9-14 h. [2]
Protein binding ~75% (plasma). [2]
After a single 50 mg dose, 6.29% excreted unchanged in urine over 24 h; mean renal clearance 9.43 mL/min. [2]
Primarily cleared by CYP3A4 metabolism; not an inhibitor of major CYP enzymes; minimal CYP3A4 induction potential. [2]
Substrate of P-glycoprotein but not OATP1B1. [2]
Food effect (high-fat meal): AUC0-∞ GMR 1.33 (90% CI 1.12-1.57); C24h GMR 1.56 (90% CI 1.28-1.91); Cmax unchanged. [2]

Hepatotoxicity
Among patients treated with doravirine, 13% reported elevated serum transaminases, but elevations exceeding 5 times the upper limit of normal were uncommon, occurring in less than 1% of cases. Patients with concurrent hepatitis B or C virus infection had a higher incidence of elevated serum transaminases during doravirine treatment, but these abnormalities were rarely severe. Doravirine has a short history of clinical use, but unlike many other non-nucleoside reverse transcriptase inhibitors, there are currently no reports of doravirine being associated with clinically observed liver injury. Probability score: E (suspected but not confirmed cause of clinically observed liver injury).

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Effects During Pregnancy and Lactation
◉ Overview of use during lactation There is currently no publicly available information regarding the use of doravirine during lactation. Alternative treatments are recommended. Achieving and maintaining viral suppression with antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load, breastfeeding should be supported if chosen. If viral load is not suppressed, pasteurized donated breast milk or formula is recommended.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Doravirine has a protein binding rate of approximately 76% in plasma.

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Doravirine (CAS#: 1338225-97-0) was generally well tolerated. Most common treatment-related adverse events: headache (12 subjects in study 1, 17 in study 2), dizziness, somnolence, nausea, fatigue. All non-serious events mild or moderate in intensity and limited duration. [1][2]
One subject receiving 120 mg once daily discontinued due to elevated AST (2.8×ULN), ALT (1.1×ULN), and CK (30.4×ULN) associated with heavy physical activity, judged possibly aggravated by doravirine. Values returned to normal. [2]
One serious adverse event (sarcoidosis) reported in a subject receiving 750 mg once daily, determined probably not drug-related (preexisting condition). [2]
No clinically significant trends in vital signs, ECGs, or laboratory safety tests. No rash or significant CNS events other than headache. [2]

[1]. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2014;58(3):1652-63.

[2]. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 2015;20(4):397-405.

[3]. Antimicrob Agents Chemother.2016 Mar 25;60(4):2241-7.

Doravirine (brand name: Pifeltro) is a prescription drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children weighing at least 77 pounds (35 kg) and meeting certain criteria determined by a healthcare provider. Doravirine must be used in combination with other HIV medications. Doravirine is an HIV-1 nonnucleoside reverse transcriptase inhibitor (NNRTI) and must be used in combination with other antiretroviral drugs. Doravirine can be used alone or as a combination therapy containing doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg). The formal approval of doravirine for the treatment of HIV-1 infection in adults who have not previously received antiretroviral therapy further expands the range of treatment options for HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor that inhibits the activity of human immunodeficiency virus type 1 (HIV-1). Doravirine is a non-nucleoside reverse transcriptase inhibitor and is used in combination with other antiretroviral drugs to treat HIV infection. The incidence of transient elevations in serum transaminases during doravirine treatment is low, but it has not been found to be associated with clinically significant acute liver injury. Doravirine is a pyridone non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus type 1 (HIV-1) infection. After oral administration, doravirine non-competitively inhibits HIV-1 reverse transcriptase (RT), thereby inhibiting HIV-1 viral replication. See also: ... See more ...

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Drug Indications
Doravirine, in combination with other antiretroviral drugs, is indicated for the treatment of adult patients with HIV-1 infection who have not previously received antiretroviral therapy. For patients with virological suppression (HIV-1 RNA below 50 copies/mL), stable antiretroviral therapy, no history of treatment failure, and no known mutations associated with doravirin resistance, this product is also suitable as an alternative to the current antiretroviral therapy.
FDA Label
Pifeltro, in combination with other antiretroviral agents, is indicated for the treatment of adults and adolescents aged 12 years and older with HIV-1 infection weighing at least 35 kg who have no prior or current evidence of resistance to NNRTIs.
Treatment of Human Immunodeficiency Virus 1 (HIV-1) Infection
Mechanism of Action

Doravirin is a pyridone nonnucleoside HIV-1 reverse transcriptase inhibitor. Reverse transcriptase is the enzyme by which the HIV virus produces DNA (cDNA) complementary to its RNA genome—this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for replication. Doravirin inhibits HIV-1 replication by noncompetitively inhibiting HIV-1 reverse transcriptase. However, doravirine does not inhibit human cellular DNA polymerase α, β, or mitochondrial DNA polymerase γ.

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Pharmacodynamics
In a phase II clinical trial evaluating doravirine (in combination with emtricitabine/tenofovir) at doses ranging from 0.25 to 2 times the recommended dose, no exposure-response relationship was found to be associated with efficacy. Furthermore, at a dose of 1200 mg (approximately 4 times the peak concentration observed after the recommended dose), doravirine did not prolong the QT interval to any clinically significant extent.

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Doravirine (CAS#: 1338225-97-0) is a novel NNRTI with potent activity against wild-type and common NNRTI-resistant HIV-1 strains (K103N, Y181C). It has a favorable resistance profile comparable to etravirine and rilpivirine and superior to efavirenz. It exhibits low potential for drug-drug interactions due to lack of CYP enzyme inhibition and weak induction. The 100 mg once-daily dose was selected for phase II/III development. [1][2]

C17H11CLF3N5O3

425.752

425.05

C, 47.96; H, 2.60; Cl, 8.33; F, 13.39; N, 16.45; O, 11.27

1338225-97-0

58460047

White to off-white solid powder

1.6±0.1 g/cm3

1.631

3.01

1

8

4

29

860

0

N#CC1=CC(OC2=C(C(F)(F)F)C=CN(CC(N3C)=NNC3=O)C2=O)=CC(Cl)=C1

ZIAOVIPSKUPPQW-UHFFFAOYSA-N

InChI=1S/C17H11ClF3N5O3/c1-25-13(23-24-16(25)28)8-26-3-2-12(17(19,20)21)14(15(26)27)29-11-5-9(7-22)4-10(18)6-11/h2-6H,8H2,1H3,(H,24,28)

3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 85 ~100 mg/mL (199.64~234.88 mM)

Solubility in Formulation 1: 2.5 mg/mL (5.87 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: 2.5 mg/mL (5.87 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)