Mar 27, 2019 a onecompartment pk model for doravirine with linear clearance from the central compartment was found to adequately describe the clinical pk of doravirine in the dose range of 6 to 200 mg and was suitable to provide individual exposure estimates for individuals with hiv1 in the phase 2b and 3 trials for subsequent exposureresponse analyses. Request pdf clinical pharmacodynamics, pharmacokinetics, and drug interaction profile of doravirine doravirine is a novel nonnucleoside reverse transcriptase inhibitor nnrti that has. Doravirine sets a new standard for nnrtis but what role. Doravirine studies efficacy, safety fda nda accepted. A coformulation of this drug with tenofovir disoproxil fumarate tdf and. On august 30, 2018, the fda approved doravirine dor in combination with nrtis for initial therapy of adults with hiv. Doravirine interacts with backbone of k103 not side chain no interaction with y181, l100, e8, k101 but v106 is key 5 reprinted with permission from feng m, et al. Oct 27, 2014 safety and efficacy of doravirine mk1439 in participants with human immunodeficiency virus 1 hiv1 mk1439018 driveforward the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Delstrigo is indicated as a complete regimen for the treatment of hiv1 infection in adult patients with no prior antiretroviral arv treatment history. Are 96week data enough for doravirine to drive forward. Doravirine dor interactions also see drug package inserts. Since k103n is by far the most prevalent in clinical practice, resistance against doravirine based antiretroviral therapies is expected to be rare, even for. Official title a phase 3 multicenter, doubleblind, randomized, active comparatorcontrolled clinical trial to evaluate the safety and efficacy of doravirine mk1439 100 mg once daily versus darunavir 800 mg once daily plus ritonavir 100 mg once daily, each in combination with truvada or epzicomkivexa, in treatmentnaive hiv1. Doravirine achieved noninferiority when compared with efavirenz and darunavirritonavirbased regimens.
Safety and efficacy of doravirine mk1439 in participants with human immunodeficiency virus 1 hiv1 mk1439018 driveforward the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Jul 25, 2018 doravirine is a new hiv1 nonnucleoside reverse transcriptase inhibitor that has demonstrated a good efficacy and safety profile in clinical trials. Nhs england doravirine for the treatment of hiv1 in adults. In august 2018, the fda approved doravine under the product name pifeltro, and in a combination tablet, doravirinelamivudinetenofovir disoproxil fumarate delstrigo. Driveahead is a phase 3, doubleblind, noninferiority trial. Class or drug mechanism of action clinical comments strong inducers or inhibitors of cyp3a deeks 2018 dor is a substrate of cyp3a, and as such, drugs that affect its metabolism affect its concentrations. Dor is being evaluated in several ongoing clinical trials both as a oncedaily singleentity tablet in combination with other antiretroviral agents in a tailored regimen, and as a oncedaily fixeddose combination dor3tctdf. Nnrti that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus hiv1 infection in phase iii clinical trials. In a shortterm monotherapy study in treatmentnaive men with hiv1 infection, doravirine 25 mg or 200 mg once daily for 7 days had robust antiviral activity, without evidence. The in vitro resistance profile suggests that, in the presence of doravirine, most viruses present mutations at positions 106, 108, 227 and 234.
We searched pubmed from inception to march 31, 2017, for clinical trials that mentioned doravirine or mk1439 and found two previous clinical trials in adults with hiv1. Accp journals american college of clinical pharmacology. Food and drug administration fda has approved two new hiv1 medicines. A literature search using the pubmed database inception to june 2019 was conducted using the. Summary of genotypic and phenotypic resistance from doravirine phase 3 clinical trials wk 48. Switching to doravirinelamivudinetenofovir disoproxil. Delstrigo, a oncedaily fixeddose combination tablet of doravirine 100 mg, lamivudine 3tc, 300 mg and tenofovir disoproxil fumarate tdf, 300 mg. Doravirine is a novel nonnucleoside reverse transcriptase inhibitor nnrti that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus hiv1 infection in phase iii clinical trials. Cyp3aenzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of pifeltrosee warnings and precautions 5.
In august 2018, the fda approved doravirine under the product name pifeltro, and in a combination tablet, doravirine lamivudinetenofovir disoproxil fumarate delstrigo. Safety and efficacy of doravirine mk1439 in participants. May 23, 2019 for doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentrationtime curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone. Clinical isolates containing the y188l substitution alone or in combination with k103n or v106i, v106a in combination with g190a and f227l, or e8k in combination with y181c and m230l showed greater than 100fold reduced susceptibility to doravirine. Nhs england will commission doravirine for the treatment of hiv1 in adults, in accordance with the criteria outlined in this document. Pifeltro is used together with other medicines to treat hiv, the virus that can cause acquired immunodeficiency syndrome aids pifeltro is. New findings from study evaluating islatravir in combination with doravirine versus delstrigo doravirine 100 mg3tc 300 mgtenofovir disoproxil fumarate 300 mg company plans to initiate phase 3 trials merck nyse.
Doravirine pifeltro treatment national hiv curriculum. Clinical trials showed greater tolerance of doravirine than older drugs in its class. Sep 23, 2019 doravirine can cause serious side effects. Doravirine is a nonnucleoside reverse transcriptase inhibitor nnrti that is well tolerated and dosed once daily, with or without food. Doravirine pifeltro approved in canada for hiv treatment. However, the number of people who will receive treatment with doravirine in clinical practice will be determined by the availability and price of alternative treatment regimens. Population pharmacokinetics of doravirine and exposure. Doravirine dor interactions also see drug package inserts nysdoh ai clinical guidelines program. Doravirinelamivudinetenofovir disoproxil fumarate is non. Since k103n is by far the most prevalent pdf clinical pharmacodynamics, pharmacokinetics, and drug interaction profile of doravirine doravirine is a novel nonnucleoside reverse transcriptase inhibitor nnrti that has. These include changes in your immune system, called immune reconstitution inflammatory syndrome or iris. It has a therapeutic profile that makes it an attractive option for treatment of hiv1 infection. Pharmaceutical, clinical, and resistance information on. The materials published on the clinical care options sites.
Mar 25, 2016 doravirine dor, formerly mk1439 is a novel nnrti that displays excellent antiviral activity against these most prevalent nnrtiassociated mutants in vitro. Doravirine sets a new standard for nnrtis but what role in. Importantly, doravirine remains active against k103n viruses in vitro, and limited clinical evidence suggests this to be the case in patients as well. Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus. Approvals based on findings from the pivotal phase 3 driveahead and driveforward trials evaluating the efficacy and safety of delstrigo and pifeltro merck nyse. Approval of both doravirine individually and the coformulated doravirinelamivudinetenofovir df tablet was based on the results of two clinical trials. Mrk, known as msd outside the united states and canada, announced the results from a phase 2b clinical trial evaluating the efficacy, tolerability, and safety of islatravir mk. In october 2018 health canada approved the use and sale of a new antihiv drug, doravirine, to be sold under the brand name pifeltro. Pifeltro doravirine is a nonnucleoside reverse transcriptase inhibitor hiv medication. These clinical findings are consistent with the in vitro activity of doravirine. A population pharmacokinetic pk model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a.
Dosing for pifeltro doravirine and delstrigo doravirine. A phase 3 multicenter, doubleblind, randomized, active comparatorcontrolled clinical trial to evaluate the safety and efficacy of doravirine mk1439 100 mg once daily versus darunavir 800 mg once daily plus ritonavir 100 mg once daily, each in combination with truvada or epzicomkivexa, in treatmentnaive hiv1 infected subjects. Pifeltro doravirine is an antiviral medicine that prevents human immunodeficiency virus hiv from multiplying in your body. Doravirine is indicated for adults with no prior antiretroviral treatment history or to replace the current antiretroviral regimen in those who have suppressed hiv1 rna less than 50 copies per ml on a stable antiretroviral regimen with no history of. Mrk, known as msd outside the united states and canada, today announced new results from the phase 3 driveahead clinical trial evaluating the efficacy and safety of delstrigo, a oncedaily fixeddose combination tablet of doravirine 100 mg, lamivudine 3tc, 300 mg and tenofovir disoproxil fumara. Dor, a new nonnucleoside reverse transcriptase inhibitor nnrti, is active against hiv that carries mutations conferring resistance to other drugs in this class clin infect dis 2018. Clinical pharmacokinetics and drug interactions of doravirine. As such, there has been an increase in the published literature regarding the pharmacokinetics of doravirine and potential for drugdrug. National institute for health and care excellence clinical.
Delstrigo is indicated as a complete regimen for the treatment of hiv1 infection in adult patients with no. There is no evidence that elderly patients require a different dose than younger adult patients see action and clinical pharmacology. Clinical isolates containing the y188l substitution alone or in combination with k103n or v106i, v106a in combination with g190a and f227l, or e8k in combination with y181c and m230l showed greater than. Dor exhibits potent antiviral activity against wildtype virus and k103n, y181c, and k103ny181c mutant viruses, with 50% inhibitory concentrations ic 50 s of 12, 21. Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 hiv1 infection. Oct 27, 2014 a phase 3 multicenter, doubleblind, randomized, active comparatorcontrolled clinical trial to evaluate the safety and efficacy of doravirine mk1439 100 mg once daily versus darunavir 800 mg once daily plus ritonavir 100 mg once daily, each in combination with truvada or epzicomkivexa, in treatmentnaive hiv1 infected subjects.
Two clinical trials were conducted in healthy subjects. Switching to dor3tctdf demonstrated a superior lipid profile compared with continuation of a ritonavirboosted pibased regimen, with a statistically significant difference between the treatment groups for both ldlc and nonhdlc at week 24 p pdf. Pifeltro is used together with other medicines to treat hiv, the virus that can cause acquired immunodeficiency syndrome aids. Review the evidence of effectiveness for doravirine. A resource for hepatologists and infectious disease specialists managing hcv andor hiv infection. This policy considered the clinical circumstances in which nhs england might commission and fund the use of doravirine for treating adults with hiv1 infection. Vision impaired people having problems accessing certain pages of a pdf file may call 301 7963634 for assistance. For doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentrationtime curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone. Doravirine suppresses common nonnucleoside reverse. As the immune system gets stronger, it may have an increased response to a. A population pharmacokinetic pk model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as. September 19, 2019 the fda approved mercks pifeltro doravirine, in combination with other antiretroviral agents for the treatment of human immunodeficiency virus hiv1 infection in adult patients to replace the current antiretroviral regimen in those who are virologically suppressed hiv1 rna less than 50 copies per ml on a stable.
Mrk, known as msd outside the united states and canada, today announced that the u. Delstrigo doravirine3tctdf and pifeltro doravirine availability and access the approvals of delstrigo and pifeltro come ahead of the original fda target action date of. Iris is a condition that sometimes occurs when the immune system begins to recover after treatment with an hiv medicine. Approval of both doravirine individually and the coformulated doravirine lamivudinetenofovir df tablet was based on the results of two clinical trials.
Doravirine mk1439, dor is an investigational nnrti being evaluated by merck for the treatment of hiv1 infection. Multiple doses of rifabutin reduce exposure of doravirine. Multiple doses of rifabutin reduce exposure of doravirine in. Fda approves mercks delstrigo doravirine lamivudine. Doravirine dor, which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus hiv1 nonnucleoside reverse transcriptase inhibitor nnrti. Merck announces week 96 data from pivotal phase 3 drive.