Pharmacotherapeutic group: Antivirals for systemic use. ATC code: J05A-E010.
Pharmacology: Pharmacodynamics: Mechanism of action: Darunavir is an inhibitor of the dimerization and of the catalytic activity of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.
Darunavir tightly binds to the HIV-1 protease with a KD of 4.5 x 10-12 M. Darunavir shows resilience to the effects of HIV protease inhibitors Resistance-Associated Mutations (RAMs). Darunavir is not an inhibitor of any of 13 tested human cellular proteases.
Pharmacokinetics: The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of alpha-1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
Absorption: Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours. The absolute oral bioavailability of a single 600 mg dose of darunair alone was approximately 37% and increased to approximately 82% in the presence of 100 mg b.i.d. ritonavir. The overall
pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg b.i.d. (see Precautions).
When administered without food, the relative bioavailability of darunavir
in the presence of low dose ritonavir is 30% lower as compared to intake with food. Therefore, darunavir tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution: Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma alpha-1-acid glycoprotein.
Metabolism: In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir/rtv dose was due to the parent drug. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wildtype HIV.
Elimination: After a 400/100 mg 14C-darunavir/rtv dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 L/h and 5.9 L/h, respectively.
Special populations: Pediatrics (17 years of age and younger): The pharmacokinetics of darunavir in combination with ritonavir in 74 treatment-experienced pediatric patients, aged 6 to < 18 years and weighing at least 20 kg, showed that the administered weight-based dosages resulted in darunavir exposure comparable to that in adults receiving darunavir/rtv 600/100 mg b.i.d. (see Dosage & Administration). Median (range) darunavir AUC12h and C0h values in this pediatric population were 61.6 (35.9-100.8) mcg.h/mL and 3.7 (1.8-7.2) mcg/mL, respectively.
Elderly (65 years of age and older): Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18-75 years) evaluated in HIV infected patients (see Precautions).
Renal impairment: Results from a mass balance study with 14C-darunavir/rtv showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 mL/min, n=20) (see Dosage & Administration and Precautions).
Hepatic impairment: Darunavir is primarily metabolized and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the steady-state pharmacokinetic parameters of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see Dosage & Administration and Precautions).
Gender: Population pharmacokinetic analysis showed a slightly higher darunavir exposure in HIV infected females compared to males. This difference is not clinically relevant.
Pregnancy and postpartum: The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg b.i.d and darunavir/ritonavir 800/100 mg q.d. as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Tables 1 and 2). However, for unbound (i.e., active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 24% and 17% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 19%, 17% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 34%, 34% and 32% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 31%, 35% and 50% lower, respectively, as compared with postpartum.
Toxicology: Non-Clinical Information: Carcinogenicity and Mutagenicity: Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450, and 1000 mg/kg were administered to mice and doses of 50, 150, and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant or rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes, and in vivo micronucleus test in mice.
Animal toxicology studies have been conducted with darunavir alone, in mice, rats, dogs, and in combination with ritonavir in rats and dogs.
In chronic toxicology studies in rats and dogs, there were only limited effects of treatment with darunavir. In the rat, the key target organs identified were the hematopoietic system, the blood coagulation system, liver, and thyroid, observed at 100 mg/kg/day and above and at exposures below clinical levels. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated PTT. The observed liver and thyroid changes were considered to reflect an adaptive response to enzyme induction in the rat rather than an adverse effect. In combination toxicity studies with ritonavir, no additional target organs of toxicity were reported in rats. In the dog, no major toxicity findings or key target organs were identified at doses up to 120 mg/kg/day and exposures equivalent to clinical exposure at the recommended dose.
Reproductive Toxicology: In a study conducted in rats, there were no effects on mating or fertility with darunavir treatment up to 1000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in humans at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone, nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In addition, rats treated with combination with ritonavir showed no teratogenicity with the increase in exposure levels which are higher than those with the recommended clinical dose in humans.
Juvenile Toxicity: In a pre and postnatal development assessment in rats, darunavir with and without ritonavir caused a transient reduction in body weight of the offspring during lactation. This was attributed to drug exposure via the milk. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats directly dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age, mortality was observed and, in some of the animals, convulsions. Within this age range, exposures in plasma, liver, and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood brain barrier. No treatment related mortalities were noted in juvenile rats dosed at 1000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats. Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir/rtv should not be used in pediatric patients below 3 years of age.
Microbiology: Antiviral activity in vitro: Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM. These EC50 values are well below the 50% cellular toxicity concentration range of 87 μM to > 100 μM.
The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir showed synergistic antiviral activity when studied in combination with the protease inhibitors ritonavir, nelfinavir, or amprenavir and additive antiviral activity when studied in combination with the protease inhibitors indinavir, saquinavir, lopinavir, atazanavir, or tipranavir,the N(t)RTIs zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, or tenofovir, the NNRTIs etravirine, nevirapine, delavirdine, rilpivirine, or efavirenz and the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of those antiretrovirals.
Resistance in vitro: In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23-50-fold) harbored 2 to 4 amino acid substitutions in the protease gene. The decreased susceptibility to darunavir of the emerging viruses.
In vitro selection of darunavir-resistant HIV-1 (range: 53-641-fold change in EC50 values [FC])from 9 HIV-1 strains harboring multiple PI RAMs resulted in the overall emergence of 22 mutations in the protease, of which L10F, V321, L33F, S37N, M461, 147V, 150V, L63P, A71 V, and 184V were present in more than 50% of the 9 darunavir-resistant isolates. A minimum of 8 of these darunavir in vitro selected mutations, from which at least 2 were already present in the protease prior to selection, were required in the HIV-1 protease to render a virus resistant (FC > 10) to darunavir.
In 1113 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir and in 886 baseline isolates from the patients enrolled in the POWER 1 and POWER 2 trials and in the POWER 3 analysis, only the subgroups with > 10 PI RAMs showed a median FC for darunavir > 10.
Cross-resistance in vitro: Cross-resistance has been observed among HIV protease inhibitors. Darunavir has a < 10-fold decreased susceptibility against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.
Seven of the 9 darunavir-resistant viruses selected from PI-resistant viruses had phenotypic data for tipranavir. Six of those showed a FC < 3 for tipranavir, indicative of limited cross-resistance between these 2 protease inhibitors.
Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors, the entry inhibitors, or the integrase inhibitors, is unlikely because the viral targets for those inhibitors are different.