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Doravirine: Newly U.S. Food and Drug Administration Approved Drug for Treating HIV1 Infection in Adult Patients

            Pifeltro is the trademark name of newly approved prescription antiretroviral agent by the U.S. Food and Drug Administration (FDA). It contains doravirine as the active agent for treating HIV-1 infections. The market status of this medication remains on prescription only basis. In addition, doravirine is a reference listed drug as well as an FDA reference standard drug (FDA, 2018_b). Doravirine is supplied as Pifeltro oral tablets at the strength of 100 mg doravirine per tablet (Prescribers’ Digital Reference (PDR), 2019). This paper provides a discussion of doravirine approval history, drug properties and mechanism, uses, adverse events, and precautions for using this drug followed by a concluding statement.

History of Approval

            Doravirine was approved by the U.S. FDA on Aug 30, 2018 under the New Drug Application number 210806. It was developed by MSD MERCK Co. Inc. The agent’s submission classification is type 1 – molecular entity. It does not inhibit human cellular mitochondrial DNA polymerase γ and DNA polymerases α and ß (FDA, 2018_a). On Nov 28, 2018, doravirine was approved by the European Medicines Agency as a fixed dose combination with lamivudine and tenofovir and a separate formulation for co-administration with other antiretroviral drugs (Collins, 2018). Similarly, doravirine was approved in the U.S. as a fixed-dose combination tablet the nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate and lamivudine and a single-agent tablet (Deeks, 2018).

Drug Properties and Mechanism of Action

            Doravirine is one of the pyridinone non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1. In other words, it is not the first agent in its class. It inhibits replication of HIV-1 through non-competitive inhibition of the HIV-1 reverse transcriptase (FDA, 2018_b). NNRTIs are antiretroviral agents that are administered as first-line treatment regimen for HIV-1 infections (Saka et al., 2018). Unlike nucleoside reverse transcriptase inhibitors, doravirine does not compete for the binding sites or require phosphorylation so as to be active. In addition, doravirine binding sites in the reverse transcriptase is different from that of the nucleoside reverse transcriptase inhibitors; whereby, these binding sites result in disruption of the enzyme’s active site thus blocking DNA-dependent and RNA-dependent DNA polymerase activities. In wild-type laboratory adapted strains, approximately12nM concentration of doravirine leads to 50% maximal inhibitory concentrations. Fortunately, doravirine does not inhibit human cellular DNA polymerase beta, alpha, and the mitochondrial gamma DNA polymerase (PDR, 2019).

            This drug is also faced by drug resistance issues. Doravirine’s in vitro resistance profile is different from other NNRTIs and tends to retains antiviral effectiveness against HIV-1 strains that are associated with most NNRTIs mutations (Soulie et al., 2018). It is potent against the most common NNRTI resistant HIV-1 variants (Molina et al., 2018). Doravirine-resistant HIV-1 strains have been detected in cell cultures. Drug-resistance is associated with the emergent of reverse transcriptase amino acid substitutions such as V106M, V106A, V108I, V106I, F227C, H221Y, F227L, M230I, F227V, P236L, L234I, and Y318F. In clinical trials, reverse transcriptase substitutions associated with doravirine resistance was detected in V106I, A98G, V106A, V108I, V106T/M, Y188L, E138K/G, P225H, H221Y, Y318F/Y, F227C, and F227R/C. After development of doravirine resistance, it increases the likelihood of cross-resistance to rilpivirine, efavirenz, nevirapine, or entravirine. Use of doravirine in patients who are infected with HIV-2 is not recommended since HIV-2 is resistant to all NNRTIs (PDR, 2019).

            Following administration via the oral route, doravirine is systematically absorbed into circulation with a volume of distribution of 60 ½ liters. The drug is 76% bound to plasma proteins; whereas, the rest exists freely in plasma. The absolute bioavailability of doravirine is 64%, whereas the maximum time necessary for it to attain this concentration is 2 hours.   Doravirine is extensively metabolized in the liver through the action of CYP3A4 enzyme. A good proportion of the drug is eliminated in metabolite form. However, 6% of the drug dose is excreted in the urine unaltered. Fecal or biliary excretion is a non-significant elimination pathway for the drug. In addition, elimination pathway of this drug is 15 hours (PDR, 2019). 

Uses

Indication, Dosage and Administration

            The new agent is indicated for use in combination with other antiretroviral therapeutics for treatment of HIV-1 infections in adult patients. However, an adult patient should have no prior exposure to antiretroviral drugs. It can be used together with non-nucleoside reverse transcriptase inhibitors such as efavirenz, delavirdine, nevirapine, entravirine, or rilpivirine. Besides, it can be used in combination with nucleoside reverse transcriptase inhibitors such as ziovudine, tenofovir DF, stavudin, lamivudine, abacavir, didanosine, emtricitabine. It can also be used in combination with HIV protease inhibitors such as indinavir and darunavir. Moreover, the drug can be used with the gp41 fusion inhibitor known as enfuvirtide, the integrase stand transfer inhibitor known as raltegravir, and the CCR5 co-receptor antagonist known as maraviroc, (FDA, 2018_b). Doravirine should never be used as a monotherapy but must be used in combination with other antiretroviral medications (PDR, 2019).

            Recommended dosage for doravirine is one tablet once daily taken via oral route without/with food in adult patients. However, if doravirine is administered together with rifabutin, then doravirine dosage is increased to one tablet taken via the oral route twice per day; about 12 hours apart. Tablet is the sole dosage form, whereas the strength is of each tablet is 100 mg doravirine (FDA, 2018_b). Special considerations in terms of maximum dosage should be adhered to when treating adults and geriatric patients. Adults should be administered with a dose of 100 mg/day by mouth or 200 mg/day by mouth if it is co-administered with rifabutin. Similarly, geriatric patients should be administered with a dose of 100 mg/day by mouth or 200 mg/day by mouth should be administered if it is co-administered with rifabutin. Efficacy and safety have not been established in other special populations such as infants, adolescents, neonates, and children. Hence, it should not be given to infants, pregnant women, adolescents, and children (PDR, 2019).

Contraindications/ Precautions

            The agent is contraindicated when it is administered with therapeutics with strong cytochrome P450 (CYP) 3A enzyme inducing effects since they lower doravirine plasma concentrations; thus decreasing its effectiveness. Contraindicated agents include the androgen receptor inhibitor enzalutamide and the anticonvulsants oxycarbazepine, carbamazepine, phenytoin, and phenobarbital. Other contraindicated drugs include St. John’s wort (Hypericum perforatum), the antimycobacterials such as rifapentine and rifampin, and the cytotoxic agent mitotane (FDA, 2018_b). The PDR’s (2019) guideline is that the agent is contraindicated when it is co-administered with strong CYP3A inducers since they can significantly decrease the effectiveness of doravirine. Co-administration of doravirine with strong CYP3A inducers such as St. John’s wort and rifampin can result in development of viral resistance and decreased effectiveness of the agent (PDR, 2019).

            Unplanned discontinuation of the drug is essential in specific circumstances. It includes severe hyperemesis gravidarum unresponsive to antiemetics, surgery or intercurrent illness (including pancreatitis and gastroenteritis), serious drug toxicity, or drug non-availability (PDR, 2019). If the interruption is short-term (1-2 days) as a result of drug toxicity, then all antiretroviral medications must be discontinued in a simultaneous manner. However, pharmacokinetic properties of other antiretroviral drugs and doravirine should be considered if the discontinuation is on a short-term basis and as a result of a surgical operation. Long term discontinuation of the drug is not recommended since there is risk of HIV disease progression characterized by viral rebound, declining CD4 counts, and acute viral syndrome, development of serious non-AIDs complications, development of minor HIV-related manifestations, increased risk of opportunistic infections, and increased risk of HIV transmission (PDR, 2019). 

Adverse Reactions and Side Effects

            The most common adverse reactions include dizziness, nausea, fatigue, headache, diarrhea, abnormal dreams, and abdominal pain (FDA, 2018_b). Adverse reactions can be classified into severe, moderate, and mild reactions. Suicidal ideation is the only known severe reactions. Moderate adverse reactions include depression, hyperbilirubinemia, hypertriglyceridemia, elevated hepatic enzymes, and hypercholesterolemia. Mild adverse reactions include nausea, dizziness, headache, abdominal pain, fatigue, nightmares, maculopapular rash, abnormal dreams, rash, diarrhea, asthenia, and insomnia (PDR, 2019).

Warnings and Precautions

            There is risk of loss of virologic response or adverse reactions due to drug interactions. Doravirine should not be taken if the patient is already using other medicines such as rifampin, carbamazepine, oxcarbazepine, rifapentine, enzalutamide, phenytoin, St. John’s wort, mitotane, and phenobarbital the patient should have not used any of the above medications for the last 4 weeks before starting treatment with doravirine. Doravirine is metabolized by CYP3A. Drugs that inhibits or induces CYP3A may affect doravirine plasma clearance. Co-administration of drugs that inhibits CYP3A can lead to elevation of doravirine plasma concentrations; whereas, those that induces CYP3A can lead to decreased plasma concentrations of CYP3A (FDA, 2018_b). However, doravirine has better safety profile than efavirenz-based regimens and has a low potential for drug-to-drug interactions (Colombier & Molina, 2018). Use of doravirine in HIV-1 treatment-naïve patients is well tolerated, with relatively fewer nominal changes in non-high density lipoprotein cholesterol and low density lipoprotein cholesterol as well as fewer neuropsychiatric events compared with emtricitabine (200mg), efavirenz (600mg), and tenofovir disoproxil fumarate (Orkin et al., 2018).

            Breastfeeding is not recommended during the treatment period since there is a potential risk of transmission of HIV-1 virus to the infant. During administration, the patient should be monitored for immune reconstitution syndrome. The immune system may get stronger and start fighting other infections that may have stayed in latent state for a long time resulting in appearance of common side effects (FDA, 2018_b).  It is not yet known if doravirine is effective and safe in children under 18 years of age. Besides, it is not yet known if doravirine use during pregnancy can harm the fetus. Hence, it should be used with caution. In addition, it is not yet clear as to whether doravirine can pass into the breast milk or not, thus breastfeeding is not recommended during treatment with this agent (FDA, 2018_b).

            No clinically significant difference in terms of doravirine pharmacokinetics has been observed based on sex, aged (18-78 years), and/or ethnicity. Besides, there is no significant difference between the pharmacokinetic profile of this drug in severe to mild renal impairment (creatinine clearance >15 mL/minute) or in cases of moderate hepatic impairment. However, the pharmacokinetics profile of doravine in patients who are undergoing dialysis, those experiencing end-stage renal disease, severe hepatic impairment, and patients who are aged under18 years remains unknown (FDA, 2018_b). No special dosing considerations are needed in case of mild to moderate hepatic impairment and/or renal impairment (PDR, 2019). The agent is stored at room temperature (68°F to 77°F (20°C to 25°C)). It must be kept in the original bottle and the bottle must be tightly closed to protect the tablets from moisture damage. This is because the bottle is packed together with a desiccant to keep the tablets dry and protect it from moisture (FDA, 2018_b). 

Conclusion

            Doravirine, trademarked Pilfeltro is a new NNRTI used as first-line treatment regimen for HIV-1. HIV-2 is resistant to doravirine. The agent is effective across demographic differences such as sex, race, and ethnicity but limited for use by persons who are 18 years by age and above and have no previous exposure to other antiretroviral treatment within a 2 month period. Caution should be observed since it should not be used by pregnant women or breast feeding due to potential passage of the drug to the fetus or passage of HIV-1 virus via the breast milk. It is not contraindicated in cases of severe to mild renal impairment or moderate hepatic impairment. However, it is contraindicated when CYP3A inducers or inhibitors are being used by the patient. The normal dose is 1 tablet (100mg) per day or 2 tablets (200mg) per day if prescribed together with rifabutin.