Pifeltro

Uses

Pifeltro is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals to treat HIV-1 infections.

Pifeltro is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

Pifeltro is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1), Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Pifeltro works

Pifeltro is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1. Reverse transcriptase is the enzyme with which HIV generates complementary DNA (cDNA) to its RNA genome - this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for the purposes of replication. Pifeltro inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase. Pifeltro does not, however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ.

Toxicity

No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or 5

No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes.

It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine.

The safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age.

Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of doravirine in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities or other drug therapy.

No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Pifeltro has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients.

No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Pifeltro has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Pifeltro was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls.

Pifeltro was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays.

There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD.

Food Interaction

• Avoid St. John's Wort. This herb induces the CYP3A metabolism of doravirine and may reduce its serum concentration. Co-administration of doravirine with St. John's Wort is contraindicated.
• Take at the same time every day.
• Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Pifeltro Drug Interaction

Minor: diltiazem, nirmatrelvir / ritonavirUnknown: lodoxamide ophthalmic, lubiprostone, bictegravir / emtricitabine / tenofovir alafenamide, alprostadil, calcium / vitamin d, testosterone, emtricitabine / tenofovir alafenamide, hydromorphone, teriparatide, phenylephrine topical, ferrous sulfate, regadenoson, dronabinol, metoprolol, magnesium hydroxide, insulin aspart, dolutegravir, cholecalciferol

Volume of Distribution

The steady-state volume of distribution of doravirine following intravenous administration is 60.5 L.

Elimination Route

The absolute bioavailability of doravirine is 64% with a T_max of 2 hours. Following oral [14C]doravirine administration, all of the administered dose was recovered and the agent is considered to be well absorbed. Moreover, its co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies.

Half Life

The elimination half-life determined of doravirine is 15 hours.

Clearance

The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively.

Elimination Route

The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism. Only 6% of an administered dose is recovered in the urine unchanged, with even less unchanged drug found in the feces.

Innovators Monograph

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