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Hovilpri (pritelivir)

Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults

Also known as AIC316
Last updated
239 sources

Product information and disease descriptionProduct descriptionProduct informationDrug/Drug, drug/disease interactions

Effects of pritelivir on other drugs

12 evidence topics · 2 sources

Breast cancer resistance protein substrates

“Pritelivir is a breast cancer resistance protein (BCRP) inhibitor. Co-administration of HOVILPRI with a BCRP substrate may increase the plasma concentrations of the BCRP substrate” (opens the prescribing information at this quote)

“which may increase the risk of adverse reactions. Refer to the prescribing information for co-administered drugs for additional information.” (opens the prescribing information at this quote)

Rosuvastatin interaction study: prescribing information

“Co-administration of multiple pritelivir doses (400 mg on Day 1 followed by 100 mg once daily on Day 2 and Day 3) with a single 20 mg oral dose of rosuvastatin (on Day 3) resulted in a 1.7-fold increase in Cmax and a 1.4-fold increase in AUC of rosuvastatin compared to rosuvastatin administered alone” (opens the prescribing information at this quote)

Changes in rosuvastatin pharmacokinetics with pritelivir: geometric mean ratio (90% CI), with and without pritelivir
Co-administered drug and regimenPritelivir regimenNAUC0-infAUC0-lastCmax
Rosuvastatin 20 mg single dose“100 mg once daily”“16”“1.37 (1.27, 1.48)”“1.41 (1.28, 1.56)”“1.67 (1.45, 1.92)”
Substrates of CYP2B6, CYP2C8, CYP2C9, CYP3A4, and OATP2B1: prescribing information

“No clinically significant changes in substrate exposures were observed in clinical drug-drug interaction trials when pritelivir was co-administered with the cytochrome P450 (CYP)2B6 substrate bupropion, the CYP2C8 substrate repaglinide, the CYP2C9” (opens the prescribing information at this quote)

“substrate flurbiprofen, the CYP3A4 substrate midazolam, and the organic anion transporting polypeptide (OATP)2B1 substrate celiprolol.” (opens the prescribing information at this quote)

In vitro enzyme and transporter studies: prescribing information
StudyPrescribing information
Cytochrome P450 inhibition“Pritelivir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at clinically relevant exposures.”
Cytochrome P450 induction“Pritelivir does not cause clinically relevant induction of CYP1A2, CYP2C9, or CYP2C19.”
Time-dependent inhibition“Pritelivir does not cause time-dependent inhibition of any CYP enzymes.”
Transporter inhibition“Pritelivir does not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K at clinically relevant exposures.”
Metabolites and cytochrome P450 inhibition“The major circulating metabolites of pritelivir, AIC090015 and AIC090105, are not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 to a clinically relevant extent.”
Organic anion transporter substrates“No clinically significant differences in the pharmacokinetics of OAT substrates are predicted when co- administered with HOVILPRI 100 mg once daily.”
In vitro findings that led to the clinical interaction trials

“In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP).” (opens the source at this quote in a new tab)

“The results of the in vitro studies indicated a potential clinically relevant effect of pritelivir on CYP2C8, CYP2C9, intestinal uptake transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1) and intestinal efflux transporter Breast Cancer Resistance Protein (BCRP) inhibition, CYP2B6 induction, and CYP3A4/5 suppression.” (opens the source at this quote in a new tab)

Clinical interaction trials with probe substrates: design

“This was a sequential, single-center, open-label phase 1 trial in 16 healthy male or female subjects. The OATP2B1 substrate celiprolol (200 mg) was administered on days 1 and 8 and a cocktail of substrates, including 10 mg flurbiprofen (CYP2C9 substrate), 20 mg bupropion (CYP2B6 substrate), and 1 mg midazolam (CYP3A4 substrate), was administered on days 3 and 19.” (opens the source at this quote in a new tab)

“A loading dose of 400 mg of pritelivir was administered on day 6, followed by once-daily administrations of 100 mg of pritelivir from day 7 to day 21, inclusive.” (opens the source at this quote in a new tab)

“This was a sequential, single-center, open-label phase 1 trial in 16 healthy male or female subjects. The CYP2C8 substrate repaglinide (0.5 mg) was administered on days 1, 7, and 20 and the BCRP substrate rosuvastatin (20 mg) was administered on days 2 and 9.” (opens the source at this quote in a new tab)

“A loading dose of 400 mg of pritelivir was administered on day 7, followed by once-daily administrations of 100 mg of pritelivir from day 8 to day 20, inclusive.” (opens the source at this quote in a new tab)

“Although it was not powered to show the absence of an effect, the generally accepted no-effect boundaries of 80%-125% for the 90% CIs for systemic exposure ratios were used for the interpretation of the results.” (opens the source at this quote in a new tab)

Clinical interaction trials with probe substrates: exposure ratios with and without pritelivir
Substrate (pathway)ParameternLeast squares means ratio (%)90% confidence interval (%)
Celiprolol (OATP2B1), excluding subject 107Cmax“15”“111.9”“86.5-144.9”
Celiprolol (OATP2B1), excluding subject 107AUC0-last“15”“113.3”“96.1-133.5”
Celiprolol (OATP2B1), excluding subject 107AUC0-inf“15”“113.1”“96.3-132.9”
Midazolam (CYP3A4)Cmax“16”“87.4”“76.7-99.7”
Midazolam (CYP3A4)AUC0-last“16”“91.8”“82.3-102.3”
Midazolam (CYP3A4)AUC0-inf“12”“97.2”“86.0-109.7”
Flurbiprofen (CYP2C9)Cmax“16”“97.9”“93.2-102.7”
Flurbiprofen (CYP2C9)AUC0-last“16”“116.3”“111.5-121.3”
Flurbiprofen (CYP2C9)AUC0-inf“16”“117.2”“112.3-122.3”
Bupropion (CYP2B6)Cmax“16”“96.3”“77.3-119.9”
Bupropion (CYP2B6)AUC0-last“16”“90.8”“81.4-101.3”
Bupropion (CYP2B6)AUC0-inf“13”“96.9”“90.2-104.1”
Repaglinide (CYP2C8), day 7, with the 400 mg loading doseCmax“16”“97.9”“80.3-119.2”
Repaglinide (CYP2C8), day 7, with the 400 mg loading doseAUC0-last“16”“115.5”“102.9-129.6”
Repaglinide (CYP2C8), day 7, with the 400 mg loading doseAUC0-inf“3”“99.4”“75.9-130.1”
Repaglinide (CYP2C8), day 20, at steady stateCmax“16”“113.2”“92.9-137.9”
Repaglinide (CYP2C8), day 20, at steady stateAUC0-last“16”“127.5”“113.6-143.1”
Repaglinide (CYP2C8), day 20, at steady stateAUC0-inf“3”“113.5”“86.6-148.5”
Rosuvastatin (BCRP)Cmax“16”“167.0”“145.2-192.0”
Rosuvastatin (BCRP)AUC0-last“16”“141.3”“128.0-155.9”
Rosuvastatin (BCRP)AUC0-inf“8”“136.9”“126.6-147.9”
Rosuvastatin: weak inhibition of intestinal BCRP

“Consistent with the in vitro results, a therapeutic 100-mg multiple once-daily regimen of pritelivir showed a weak inhibitory potential on the intestinal efflux transporter BCRP (<2-fold).” (opens the source at this quote in a new tab)

“When combined with 400 mg of pritelivir on day 7 followed by 100 mg once daily on day 9, the LSmeans ratios for Cmax, AUC0-last, and AUC0-inf of rosuvastatin were increased (167.0, 141.3, and 136.9, respectively) and the lower bound of the CI exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab)

“Although there is no standard classification for the effects of transporter inhibitors, the increase in rosuvastatin is analogous to weak inhibition in the scenario of CYP inhibition with a sensitive substrate.” (opens the source at this quote in a new tab)

Repaglinide: CYP2C8 after the loading dose and at steady state

“For CYP2C8 (repaglinide), there was no clinically relevant inhibition observed when combined with the 400 mg loading dose of pritelivir.” (opens the source at this quote in a new tab)

“When combined with 100 mg pritelivir at steady state, there was no net induction of CYP2C8 activity, but as the upper bound of the 90% CIs exceeded the 125% no-effect boundary, a weak net inhibition of CYP2C8 cannot be excluded.” (opens the source at this quote in a new tab)

“However, as the LSmeans ratio for Cmax was far below 125% (113.2%) and the LSmeans ratio for AUC0-last was just above 125% (127.5%), this is likely not of clinical relevance.” (opens the source at this quote in a new tab)

Midazolam, flurbiprofen, bupropion, and celiprolol: CYP3A4, CYP2C9, CYP2B6, and OATP2B1

“The results from the 2 trials indicate no clinical interaction potential of pritelivir for CYP3A4 (suppression), CYP2C9 (inhibition), and CYP2B6 (induction) as AUC0-last and AUC0-inf of the respective substrates midazolam, flurbiprofen, and bupropion were within the 80%-125% no-effect boundaries.” (opens the source at this quote in a new tab)

“For midazolam and bupropion Cmax, the lower bound of the 90% CI was slightly below the 80% no-effect boundary.” (opens the source at this quote in a new tab)

“Furthermore, no inhibition of the intestinal uptake transporter OATP2B1 was observed.” (opens the source at this quote in a new tab)

“This did not affect the interpretation of the results, since pritelivir is not an inhibitor or inducer of P-gp.” (opens the source at this quote in a new tab)

Overall conclusion of the clinical interaction trials

“In conclusion, a therapeutic 100-mg multiple once-daily regimen of pritelivir had no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 (celiprolol) and the cytochrome P450 enzymes 3A4 (midazolam), 2B6 (bupropion), 2C9 (flurbiprofen), and 2C8 (repaglinide).” (opens the source at this quote in a new tab)

“However, it showed a weak inhibitory potential on the intestinal efflux transporter BCRP.” (opens the source at this quote in a new tab)

“Overall, the results indicate that pritelivir has a low DDI potential.” (opens the source at this quote in a new tab)