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Darunavir Darunavir 300 Prezista 400mg Prezista 400mg Prezista 600mg Prezista 600mg
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Brand Name: Prezista  Audio
Drug Class: Protease Inhibitors

Drug Description
Darunavir, also known as TMC114, is a nonpeptidic protease inhibitor (PI) containing 3(R),3a(S),6a(R)-bis-tetrahyrofuranyl urethane (bis-THF) and a sulfonamide isotere.[1]

HIV/AIDS-Related Uses
Darunavir was granted accelerated approval by the FDA on June 23, 2006, for use in combination with other antiretroviral agents for the treatment of HIV infection in adults.[2] It is indicated for the treatment of HIV infection in antiretroviral-treatment--experienced adults, such as those infected with HIV-1 strains resistant to more than one PI.[3] An ongoing Phase III trial also is studying the use of darunavir combined with ritonavir in patients with less advanced disease than those previously studied.[4] The 48-week results of this study suggest that in these patients, darunavir is as effective as other antiretroviral agents and that in patients with viral loads about 100,000 copies/ml, darunavir is more effective that lopinavir boosted with ritonavir.[5] Based on this trial, darunavir was granted traditional approval on October 21, 2008. [6]

Darunavir is a second-generation PI that is highly active in vitro against both wild-type and PI-resistant HIV. Darunavir is viewed as a potential substitute for PIs currently used in the treatment of HIV.[7] Darunavir must be coadministered with a low-dose ritonavir booster.[8]

The manufacturer provides darunavir through an ongoing expanded access program (EAP) for patients outside of the United States who have limited or no treatment options because of virologic failure or because of intolerance to multiple antiretroviral regimens. Patients and health care professionals can visit http://www.tibotec.com or call 1-877-732-2488 for more information.[9]

Dosing Information

Mode of Delivery
Oral.[10]

Dosage Form
Tablets containing 400 or 600 mg darunavir.[11][12]

In treatment-experienced adults, the recommended daily dose of darunavir is 600 mg taken with ritonavir 100 mg twice daily with food.[13] In treatment-naive adults, the recommended daily dose of darunavir is 800 mg (two 400-mg tablets) with ritonavir 100 mg taken once daily with food. [14]

If a patient misses a dose of darunavir and ritonavir by more than 6 hours, the patient should be told to wait and then take the next dose of darunavir and ritonavir at the regularly scheduled time. If the patient misses a dose by less than 6 hours, the patient should be told to take darunavir and ritonavir immediately then to take the next dose at the regularly scheduled time. If a dose of darunavir and ritonavir is skipped, the patient should not double the next dose. Patients should not take more or less than the prescribed dose of darunavir or ritonavir at any one time.[15]

Storage
Store tablets at 25 C (77 F); excursions permitted at 15 C to 30 C (59 F to 86 F).[16]

Pharmacology
Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.[17] The promising virologic profile of darunavir is the result of its unique chemical structure. The potency of darunavir against multidrug-resistant viruses is believed to be due to a combination of its flexibility, extremely high affinity, and close fit within the substrate envelope.[18]

Evidence of efficacy of darunavir and ritonavir in antiretroviral-treatment-experienced, HIV infected adults has been shown in analyses of interim 24-week data in two randomized, Phase IIb trials, TMC114-C213 and TMC114-C202. Both of these trials consisted of two parts: an initial, partially blinded, dose-finding part and a second, long-term part, in which all patients were randomly assigned to either darunavir and ritonavir or to an investigator-selected, comparator PI-arm, antiretroviral regimen and then received the recommended dose of darunavir 600 mg and ritonavir 100 mg. Participants had a baseline HIV RNA of greater than 1,000 copies/ml; had previous treatment with PIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase inhibitors (NRTIs); had at least 1 primary PI mutation at screening, and had to be currently taking a stable PI-containing regimen at screening for at least 8 weeks prior to study entry. Analyses included 318 patients in TMC114-C213 and 319 patients in TMC114-C202. At Week 24, the virologic response rate was evaluated in patients receiving darunavir and ritonavir plus an optimized background regimen (OBR) versus a control group receiving an investigator-selected PI-containing regimen plus an OBR.[19] Through 24 weeks of treatment, the proportion of patients whose viral load was less than 400 copies/ml in the arm receiving darunavir and ritonavir compared with the comparator PI arm was 63% and 19%, respectively. In addition, the fold changes of plasma viral load from baseline were nearly 100-fold in the arm receiving darunavir and ritonavir and approximately 3-fold in the comparator PI arm. The mean increase from baseline in CD4 cell counts was greater in the arm receiving darunavir and ritonavir (92 cells/mm3) than in the comparator PI arm (17 cells/mm3).[20]

The absolute oral bioavailability of a single 600-mg dose of darunavir alone and after coadministration with ritonavir 100 mg twice daily was 37% and 82%, respectively. Darunavir coadministered with ritonavir 100 mg twice daily was absorbed following oral administration with a time to peak plasma concentration (Tmax) of approximately 2.5 to 4 hours. When administered with food, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of darunavir coadministered with ritonavir is approximately 30% greater than in the fasting state. Therefore, darunavir coadministered with ritonavir should always be taken with food. Within the range of meals studied, darunavir exposure is similar.[21] In a study of 119 HIV infected patients, the mean 12-hour AUC was 61,668 ng(h)/ml with darunavir 600 mg and ritonavir 100 mg twice-daily dosing. The median concentration at time of administration was 3,539 ng/ml.[22]

The pharmacokinetics of darunavir have been studied in Phase II trials in healthy volunteers and in PI-experienced patients.[23][24] In healthy volunteers, darunavir was rapidly absorbed; the time to maximum plasma concentration (Cmax) was 3 hours. Steady-state concentrations were reached within 3 days. Increasing doses of darunavir were administered alone or with ritonavir. Darunavir with ritonavir had a more favorable pharmacokinetic profile compared to darunavir alone. In the unboosted trial, the minimum plasma concentration (Cmin) at Day 14 ranged from 14 ng/ml to 142 ng/ml as the darunavir dose increased. Cmax ranged from 2,168 ng/ml to 8,040 ng/ml. In the ritonavir-boosted trial, Cmin at Day 14 ranged from 480 ng/ml to 1,486 ng/ml and Cmax ranged from 1,569 ng/ml to 5,453 ng/ml.[25]

Darunavir is in FDA Pregnancy Category C. There are no adequate and well-controlled studies conducted in pregnant women. Reproduction studies conducted with darunavir have shown no embryotoxicity or teratogenicity in mice, rats, or rabbits. Because of the limited bioavailability of darunavir in animals or because of dosing limitations, the AUCs were approximately 50% in mice and rats and 5% in rabbits of AUC in humans at the recommended clinical dose when boosted with ritonavir.[26] In a rat pre-and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was because of exposure of the pups to drug substances via mother's milk. Sexual development, fertility, and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.[27] To monitor maternal-fetal outcomes of pregnant women exposed to antiretrovirals such as darunavir, an Antiretroviral Pregnancy Registry has been established. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether darunavir is excreted in human milk; it is excreted in the milk of lactating rats. Because of the potential for HIV transmission and for serious adverse effects from darunavir to the breastfed infant, women should be instructed not to breastfeed while taking darunavir.[28]

Darunavir binds primarily to plasma alpha 1-acid glycoprotein. Darunavir is approximately 95% bound to plasma proteins. In vitro experiments with human liver microsomes indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by cytochrome P450 (CYP) enzymes, primarily by CYP3A. At least three oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV. A mass-balance study in healthy volunteers showed that, after single-dose administration of 14-C-darunavir 400 mg coadministered with ritonavir 100 mg, the majority of the radioactivity in plasma resulted from darunavir.[29] In the same mass-balance study, approximately 79.5% and 13.9% of the administered dose of 14-C darunavir was recovered in the feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when darunavir was taken with ritonavir. After IV administration, the clearance of darunavir, administered alone and coadministered twice daily with ritonavir 100 mg, was 32.8 l/h and 5.9 l/h, respectively.[30] As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely they will be significantly removed by hemodialysis or peritoneal dialysis.[31]

In analyses of three different Phase IIb studies using darunavir, multiple PI-resistant HIV-1 isolates were collected from highly treatment experienced patients who received darunavir 600 mg and ritonavir 100 mg twice daily and experienced virologic failure either by rebound or by never being fully suppressed. These patients developed amino acid substitutions that were associated with decreased susceptibility to darunavir. The amino acid substitution V32I developed in greater than 20% of virologic failure isolates. Other substitutions that developed in 10% to 20% for darunavir and ritonavir virologic failure isolates occurred at amino acid positions I15, L33, I47, G73, and L89. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 21-fold at baseline and 94-fold at failure. Amino substitutions were also observed at the protease cleavage sites of some isolates causing virologic failure.[32]

Data from the POWER 1 and 2 Phase IIb trials that were conducted in treatment-experienced patients were pooled at Week 48 to provide further safety and efficacy results of the recommended dosage of darunavir 600 mg and ritonavir 100 mg given twice daily. At Week 48, 61% of patients in the darunavir and ritonavir arm achieved a 90% reduction in viral load, compared with only 15% of patients in the control PI arm. Viral load levels below 50 copies/ml were achieved in 45% of the treatment arm and in 10% of the control arm.[33]

The TITAN trial is an ongoing, open-label, Phase III trial to evaluate the efficacy and safety of darunavir and ritonavir in HIV infected patients who are not heavily treatment experienced. The enrolled population is intended to reflect a practical, real-life population that includes patients who previously underwent treatment interruptions and patients with less advanced disease. The recommended, twice-daily dosage of darunavir 600 mg plus ritonavir 100 mg in the treatment arm is being compared with lopinavir/ritonavir 400/100 mg twice daily in the control arm. The primary endpoint of darunavir noninferiority to lopinavir/ritonavir was established at Week 48 analysis. The secondary endpoint of darunavir superiority to lopinavir/ritonavir was supported by significant differences in viral load levels and virological failure rates in the two arms. At Week 48, 77% of patients in the treatment arm achieved viral load levels less than 400 copies/ml, compared with 68% of those in the control arm; 71% of treatment-arm patients achieved viral load levels less than 50 copies/ml, compared with 60% of control-arm patients. Only 1% of patients in the treatment arm discontinued treatment because of virologic failure, compared with 11% of patients in the lopinavir/ritonavir arm.[34]

In the Phase III trial TMC114-C211, 639 antiretroviral-naïve patients were randomly assigned to receive darunavir and ritonavir with background therapy of emtricitabine and tenofovir or lopinavir boosted with ritonavir with the same background therapy. At Week 48, the trial found that both regimens are equally effective in achieving an undetectable viral load in these treatment-naïve individuals. However, in those patients who started the trial with a viral load of 100,000 copies/ml or more, darunavir and ritonavir was more effective than lopinavir with ritonavir.[35]

In the Phase III ARTEMIS study, ritonavir-boosted darunavir was noninferior to lopinavir/ritonavir at 48 weeks. Week 96 data suggest that ritonavir-boosted darunavir is more effective at virologic suppression than lopinavir/ritonavir (achieved in 79% and 71% of patients in the darunavir and lopinavir/ritonavir arms, respectively) and leads to fewer virologic failures. In addition, significantly better responses were seen with boosted darunavir than with lopinavir/ritonavir in patients with baseline CD4 counts less than 200 cells/mm3 or viral loads greater than 100,000 copies/mL.[36][37][38]

In postmarketing studies of darunavir combined with ritonavir in 38 individuals with limited or no treatment options, 54% achieved a viral load less than 50 copies/ml after 12 weeks, and 50% achieved undetectable viral levels after 24 weeks. Mean viral load decreased more than 100-fold by Week 24.[39]

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 (PBMCs), and human monocytes/macrophages with median effective concentration (EC50) values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/ml). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 groups M and O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum.[40]

HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from people treated with darunavir and ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV had 6- to 21-fold decreased susceptibility to darunavir and harbored 3 to 6 of these amino acid substitutions in protease: S37N/D, R41E/S/T, K55Q, K70E, A71T, T74S, V77I, I85V. Selection in cell culture mutations resulted in the overall emergence of 22 mutations in the protease gene. These darunavir-resistant viruses had at least 8 protease mutations at exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.[41]

Cross resistance to other PIs has been observed. Darunavir had a less than 10-fold decreased susceptibility in cell culture against 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir, showing that viruses resistant to these PIs remain susceptible to darunavir. Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir in cell culture. However, 6 of 9 darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed a less than 3-fold change in EC50 values for tipranavir, indicative of limited cross resistance between darunavir and tipranavir. Of the viruses isolated from patients experiencing virologic failure taking darunavir 600 mg and ritonavir 100 mg twice daily, greater than 50% were still susceptible to tipranavir, whereas less than 5% were susceptible to the other PIs.[42]

Cross resistance between darunavir and NNRTIs, NRTIs, or fusion inhibitors is unlikely because the viral targets are different.[43]

Adverse Events/Toxicity
The most common treatment-emergent adverse events reported with the use of darunavir were diarrhea, nausea, headache, and nasopharyngitis.[44] (Because of the requirement for coadministration of ritonavir with darunavir, see the individual drug record for ritonavir for more information about potential adverse effects.) Abnormal liver and pancreatic function tests, abnormally high cholesterol and triglyceride levels, and decreases in white blood cell counts have also been reported.[45] Severe skin rash, including erythema multiforme and Stevens-Johnson syndrome, were reported during the development program of darunavir. In people participating in clinical trial with darunavir, fever and elevated transaminase levels have also been observed.[46]

Darunavir administered with ritonavir should be used with caution with patients with hepatic impairment, as darunavir is primarily metabolized by the liver. When darunavir was coadministered with ritonavir during the clinical development program (i.e., clinical trial and postmarketing data collection), drug-induced hepatitis occurred in 0.5% of patients. Liver injury, including fatality, that was identified in postmarketing data typically was associated with patients on multiple medications or with those who have hepatitis coinfection or immune reconstitution syndrome; causation from darunavir and concomitant ritonavir has not been established. Patients with pre-existing liver dysfunction---including chronic active hepatitis, cirrhosis, or pretreatment elevated liver enzyme levels---have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should receive increased monitoring of liver function tests, especially during the first months of darunavir and ritonavir coadministration. If there is evidence of worsening of liver disease (i.e., significant elevation of liver enzymes, anorexia, nausea, jaundice, dark urine, liver tenderness, or hepatomegaly) in such patients, interruption or discontinuation of treatment must be considered.[47][48][49][50]

Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy.[51]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including darunavir. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jiroveci pneumonia, or tuberculosis. Symptoms of immune reconstitution syndrome necessitate further evaluation and treatment.[52]

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.[53]

The safety and tolerability of TMC114/r were evaluated in treatment-experienced patients taking doses of 400/100 mg once or twice daily, 800/100 mg once daily, or 600/100 mg twice daily. Most adverse events and laboratory abnormalities were mild to moderate and occurred with similar incidence across all groups, including a control PI group. The three most common adverse events in the 600/100 mg twice-daily group were diarrhea, nausea, and headache; all three occurred with similar or less incidence than the control group. Overall, headache and diarrhea were the most common adverse reactions. Grade 3/4 reactions occurred in approximately 25% of each treatment and control group and included abnormal triglyceride, total cholesterol, and hepatic enzyme elevations. No differences were observed between treatment and control groups in overall adverse events, severe adverse events, or laboratory abnormalities.[54][55]

In the analysis at Week 48 of 324 patients receiving darunavir 600 mg and ritonavir 100 mg combined with an optimized background regimen in the POWER 3 open-label study, a Grade 3 or 4 laboratory event was observed in 25% of patients. Abnormal laboratory reports included high amylase, triglyceride, blood sugar, and cholesterol levels and high liver function test results.[56]

In postmarketing studies of darunavir combined with ritonavir, mild rash and nausea, abnormal bilirubin and cholesterol levels, and abnormal liver function tests have been observed.[57] These studies also reported rare events of hypersensitivity including facial edema and rhabdomyolysis associated with coadministration with HMG-CoA reductase inhibitors.[58]

Drug And Food Interactions
Darunavir must always be taken with ritonavir 100 mg in combination with other antiretroviral drugs.[59]

Coadministration of darunavir and ritonavir with efavirenz caused a decrease in darunavir AUC by 13% and minimum serum concentrations (Cmin) by 31%, whereas the AUC and Cmin of efavirenz increased by 21% and 17%, respectively. The clinical significance has not been established; however, this combination of drugs should be used with caution.[60]

Because didanosine must be administered on an empty stomach, didanosine should be administered 1 hour prior to or 2 hours after darunavir and ritonavir dosed with food.[61]

Coadminstration of darunavir and ritonavir with indinavir resulted in a serum concentration increase in both darunavir and indinavir. The appropriate dose of indinavir in combination with darunavir and ritonavir has not been established.[62]

Coadminstration of darunavir with lopinavir/ritonavir resulted in a 53% decrease in darunavir AUC. Coadminstration of darunavir and ritonavir with saquinavir resulted in a 26% decrease in darunavir AUC. Coadministration of these drugs with darunavir is not recommended.[63]

Both darunavir and ritonavir are inhibitors of CYP3A. Coadministration of darunavir and ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse effects.[64]

Phenobarbital, phenytoin, and rifampin are inducers of CYP450 enzymes and should not be used in combination with darunavir and ritonavir. St. John's wort should also not be used concomitantly with darunavir and ritonavir. Coadministration of these drugs may cause significant decreases in darunavir plasma concentrations and a loss of therapeutic effect to darunavir.[65] The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating coadministration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. [66]

Use of some HMG-CoA reductase inhibitors, including lovastatin and simvastatin, may require dose adjustment if taken concurrently with darunavir and ritonavir because of the potential of serious reactions such as myopathy, including rhabdomyolysis.[67] Coadminstration of darunavir and ritonavir with other HMG-CoA reductase inhibitors, such as atorvastatin and pravastatin, should be given at the lowest possible statin dose with careful patient monitoring.[68] Post marketying experience report rare events of hypersensitivity including facial edema and rhabdomyolysis associated with coadministration with HMG-CoA reductase inhibitors.[69]

Caution must be used when antiarrhythmics, including bepridil, lidocaine, quinidine, and amiodarone, are used concurrently with darunavir and ritonavir. Concentrations of antiarrhythmic drugs may increase. Therapeutic concentration monitoring should be used, if available, to guide patient treatment.[70]

Concurrent use of darunavir and ritonavir with warfarin may decrease warfarin plasma concentrations, and patients should be monitored carefully if they are taking such a regimen.[71]

Concomitant use of trazodone and darunavir and ritonavir may increase plasma concentrations of trazodone, leading to nausea, dizziness, hypotension, and syncope. A lower dose of trazodone should be considered in patients who require this combination of drugs.[72]

Concurrent use of darunavir and ritonavir with clarithromycin may require adjustment of the clarithromycin dose in patients with impaired renal function.[73]

Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Plasma concentrations of these two drugs may increase in the presence of darunavir and ritonavir. When coadministation is required, the daily dose of azole should not exceed 200 mg.[74] Concurrent use of darunavir and ritonavir with voriconazole has not been studied. However, concomitant use of voriconazole and ritonavir 100 mg twice daily decreased voriconazole AUC by 39%. Therefore, patients receiving darunavir and ritonavir should not receive voriconazole unless the potential benefit outweighs the risk to the patient.[75]

Rifabutin is an inducer and substrate of CYP450 enzymes. Concomitant use of rifabutin with darunavir and ritonavir is expected to increase rifabutin plasma concentrations. It is recommended to administer rifabutin at a maximum dosage of 150 mg rifabutin once every other day when coadministered with darunavir and ritonavir.[76][77]

Plasma concentrations of calcium channel blockers, including felodipine, nifedipine, and nicardipine, may increase when given concurrently with darunavir and ritonavir. Caution is warranted and clinical monitoring of patients is recommended.[78]

Plasma concentrations of immunosuppressants, including cyclosporine, tacrolimus, and sirolimus, may be increased when coadministered with darunavir and ritonavir. Therapeutic concentration monitoring for the immunosuppressive agent is recommended when these drugs are taken concurrently.[79]

When methadone is coadministered with darunavir and ritonavir, patients should be monitored for abstinence syndrome, as ritonavir is known to induce the metabolism of methadone, leading to a decrease in methadone's concentrations. An increase in methadone dosage may be considered based on the clinical response.[80]

Plasma concentrations of ethinyl estradiol may be decreased when it is used with darunavir and ritonavir due to the induction of its metabolism by ritonavir. Alternative or additional contraceptive measures should be used when estrogen-based contraceptives are coadministered with darunavir and ritonavir.[81]

Concomitant administration of darunavir and ritonavir with PDE-5 inhibitors, including sildenafil, vardenafil, and tadalafil, should be done with caution. PDE-5 inhibitor dosing should not exceed the doses as indicated by the manufacturer.[82]

Darunavir and ritonavir with selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine should be taken concomitantly with caution. The recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline and paroxetine who start treatment with darunavir and ritonavir should be monitored for antidepressant response.[83]

Darunavir combined with ritonavir has been shown to increase levels of concurrently administered maraviroc up to fourfold. Such a combination requires reducing the maraviroc dose by at least half for coadministration. CYP3A inhibition by ritonavir is a likely mechanism for the interaction.[84]

Contraindications
Darunavir must always be taken with ritonavir 100 mg in combination with other antiretroviral drugs.[85]

Both darunavir and ritonavir are inhibitors of CYP3A. Coadministration of darunavir and ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse effects.[86]

Caution should be used when darunavir is prescribed to patients with known sulfonamide allergies.[87]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Darunavir.

Chemistry

CAS Name
(3R,3aS,6aR)-Hexahydrofuro(2,3-b)furan-3-yl N-((1S,2R)-1-benzyl-2-hydroxy-3- (N1-isobutylsulfanilamido)propyl)carbamate[88]

CAS Number
206361-99-1[89]

Molecular Formula
C27-H37-N3-O7-S[90]

Elemental Composition
C59.2%,H6.8%,N7.7%,O20.5%,S5.8%[91]

Molecular Weight
593.73[92]

Physical Description
White to off-white powder.[93]

Solubility
Approximately 0.15 mg/ml in water at 20 C.[94]

Other Names
TMC114[95]

Further Reading
Prezista Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.

PMID/17646561 Busse KH, Penzak SR. Darunavir: a second-generation protease inhibitor. Am J Health Syst Pharm. 2007 Aug 1;64(15):1593-602.

PMID/17617272 Madruga JV, Berger D, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, Norris D, Lefebvre E, de Bethune MP, Tomaka F, De Pauw M, Vangeneugden T, Spinosa-Guzman S; TITAN study group. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007 Jul 7;370(9581):49-58.

PMID/17696797 Molina JM, Hill A. Darunavir (TMC114): a new HIV-1 protease inhibitor. Expert Opin Pharmacother. 2007 Aug;8(12):1951-64.

PMID/17720661 Rachlis A, Clotet B, Baxter J, Murphy R, Lefebvre E. Safety, Tolerability, and Efficacy of Darunavir (TMC114) with Low-Dose Ritonavir in Treatment-Experienced, Hepatitis B or C Co-infected Patients in POWER 1 and 3. HIV Clin Trials. 2007 Jul-Aug;8(4):213-20.

PMID/17713972 Rittweger M, Arasteh K. Clinical pharmacokinetics of darunavir. Clin Pharmacokinet. 2007;46(9):739-56.

Manufacturer Information
Darunavir
  Tibotec
  1029 Stony Hill Road
  Suite 300
  Yardley,  PA  19067
  (877) 732-2488
    

Prezista
  Tibotec
  1029 Stony Hill Road
  Suite 300
  Yardley,  PA  19067
  (877) 732-2488
    

References
[1] Conf Retroviruses Opportunistic Infect - 10th, 2003. Abstract 553.
[2] FDA - Prezista Approval Letter. Available at: http://www.fda.gov/cder/foi/appletter/2006/021976s000LTR.pdf. Accessed 08/30/07.
[3] Tibotec - Prezista Prescribing Information, October 2006, p. 8. Available at: http://www.prezista.com/prescribing_information.html. Accessed 08/30/07.
[4] HIV and Hepatitis.com - Conference Coverage: 4th IAS Conference on Pathogenesis, Treatment, and Prevention (July 2007)-48-week Efficacy and Safety of Darunavir (Prezista) Boosted with Ritonavir versus Lopinavir/ritonavir (Kaletra) in Treatment-experienced HIV Patients: The TITAN Trial. Available at: http://www.hivandhepatitis.com/2007icr/ias/docs/072707_b.html. Accessed 08/30/07.
[5] Interscience Conf on Antimicrobial Agents and Chemotherapy - 47th, 2007. Abstract H-718B. Available at: http://www.icaac.org/accepted-abstracts.asp. Accessed 11/21/07.
[6] FDA - HIV/AIDS Update - Important information about Prezista (darunavir). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on: 10/22/08.
[7] Conf Retroviruses Opportunistic Infect - 10th, 2003. Abstract 553.
[8] Tibotec - Prezista Prescribing Information, October 2006, p. 8. Available at: http://www.prezista.com/prescribing_information.html. Accessed 08/30/07.
[9] Tibotec - HIV: EAP. Available at: http://www.tibotec.com/bgdisplay.jhtml?itemname=EAP2. Accessed 08/30/07.
[10] Tibotec - Prezista Prescribing Information, October 2006, p. 22. Available at: http://www.prezista.com/prescribing_information.html. Accessed 08/30/07.
[11] Tibotec - Prezista Prescribing Information, October 2006, p. 22. Available at: http://www.prezista.com/prescribing_information.html. Accessed 08/30/07.
[12] FDA - HIV/AIDS Update - Important information about Prezista (darunavir). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed on: 10/22/08.
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Updated November 23, 2008