Darunavir (TMC114) Approved by the FDA

Special Feature

By Dean L. Winslow, MD, FACP

Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine

Dr. Winslow is a consultant for Bayer Diagnostics, and is on the speaker's bureau for GlaxoSmithKline and Pfizer.

This article originally appeared in the October 2006 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Dr. Price reports no financial relationship relevant to this field of study.

Darunavir (known during development as TMC114 and given the proprietary name, PREZISTA-TM) was approved by FDA on June 23, 2006, for use in combination with other antiretroviral agents for the treatment of HIV infection in adults.1 Darunavir is currently labeled for use only in treatment-experienced adults at the present time, since the clinical trials submitted to FDA to date were limited to this patient population.2 It is administered with low-dose ritonavir. Adult dosing is generally darunavir 600 mg/ritonavir 100 mg administered b.i.d.

Chemistry: Darunavir's nonpeptidic protease inhibitor (PI), has a molecular weight of 593.73, and is a sulfonamide isostere. Isosteres are compounds that have the same number of valence electrons and in the same configuration, but differing in the kinds and numbers of atoms. It is supplied as a 300 mg tablet formulation.

Preclinical toxicology: Reproduction studies show no embryotoxicity in mice, rats, or rabbits. However, darunavir is FDA Pregnancy Category B since no adequate and well-controlled studies have been conducted in pregnant women.

Human Pharmacology: Darunavir has absolute bioavailability of 37% after single-dose administration of 600 mg, and bioavailability increases to 82% when administered with ritonavir. Tmax is reached at 2.5-4 hours, and AUC is approximately 30% higher when administered with food. Darunavir is approximately 95% protein bound, and binding is primarily to alpha-1-acid glycoprotein. Darunavir undergoes oxidative metabolism by the cytochrome P450 system, mainly via the CYP3A isoform. A mass balance study in healthy volunteers showed 79.5% and 13.9% of C14-labeled darunavir recovered in the stool and urine, respectively. No data exist on the use of darunavir in patients with varying degrees of hepatic impairment; therefore, the package insert advises caution when using in patients with liver disease. The package insert provides numerous tables showing various drug interactions. In view of darunavir's known route of metabolism, as well as the need to co-administer darunavir with ritonavir, the usual boosted PI drug interactions and precautions apply.

Preclinical Microbiology: Darunavir has potent in vitro activity against wild type HIV, with EC50 ranging from < 0.1-4.3 nM. Darunavir-resistant virus selected in vitro from wild type HIV-1 showed 6- to 21-fold decreased susceptibility to darunavir and contained 3-6 of the following substitutions in protease: S37N/D, R41E/S/T, K55Q, K70E, A71T, T74S, V77I, or I85V. Numerous additional amino acid substitutions (most often L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V) were seen when HIV strains, with pre-existing PI resistance, were passed serially in vitro with darunavir, and virus containing at least 8 substitutions exhibited 50- to 641-fold reduced susceptibility to darunavir.

Clinical Efficacy: FDA approval was based on pooled analysis of treatment-experienced adult patients from 2 randomized, controlled trials of optimized best regimen (OBR) plus darunavir/r vs OBR plus an investigator-selected comparator PI. Patients in these trials had HIV-1 RNA > 1000 copies/mL, had prior PI treatment, and had at least one primary PI substitution (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening. The primary analysis was conducted at 24 weeks, and demonstrated that 45% vs 12.1% of patients had HIV RNA levels of < 50 copies/mL in the darunavir vs comparator PI arms.

Baseline Genotype/Phenotype and Virologic Outcome Analyses: Baseline substitutions V32I, I47V, or I54L/M were associated with decreased virologic response in vivo. In addition, diminished virologic response was observed in patients with ≥ 7 PI substitutions at 30, 32, 36, 46, 47, 48, 50, 53, 54, 73, 82, 84, 88, or 90. Additional analyses suggested that presence at baseline of 3 or more of the following substitutions was associated with decreased virologic response: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, or L89V. Response was proportionately less as the number of these substitutions present at baseline was greater. (It should be noted that these data simply report observed associations and include both true resistance-producing substitutions and compensatory substitutions. Sorting out which of these are truly important from a mechanistic standpoint will require time-intensive experiments using site directed mutagenesis, where specific mutations and combinations are engineered into an infectious molecular clone of HIV.) When the sponsor looked at baseline phenotypic susceptibility to darunavir (using shift in IC50 compared to a reference standard), patients with baseline susceptibility of 0-2X had 60% achieved HIV RNA < 50 copies/mL at week 24; >2-7X (47%), >7-30X (24%), and >30X (18%).

Cross-resistance: Since darunavir is currently restricted for use in treatment-experienced patients, concern about proper sequencing of darunavir vs tipranavir is of obvious interest to clinicians. Darunavir has < 10X decreased susceptibility in cell culture against 90% of 3309 clinical isolates of HIV-1 resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. While darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir in cell culture, 6 or 9 darunavir-resistant viruses selected in cell culture retained in vitro susceptibility to tipranavir. Of the viruses isolated from patients experiencing virologic failure on darunavir/ritonavir in the clinical trials, > 50% retained in vitro susceptibility to tipranavir while < 5% were susceptible to other PIs. These data suggest that a significant proportion of individuals failing therapy with tipranavir could experience a good virologic response in vivo to darunavir, and imply that at least some patients who fail darunavir could still respond to tipranavir.

Adverse Reactions: Gastrointestinal side effects of darunavir were similar to the comparator PI arm in the controlled trials. Elevations in transaminases appeared to be slightly less frequent with darunavir than with the comparator PI. Hematologic effects of darunavir were comparable to the comparator PI. Hypertriglyceridemia was comparable to the control arm. Grade 2-4 hypercholesterolemia was seen more frequently in the darunavir arm than in the comparator arm (9.2% vs 3.3%); however, the high frequency of hyperbilirubinemia in the comparator arm suggests that atazanavir was frequently used as the comparator PI, and it is known that atazanavir causes less frequent hyperlipidemia than other commonly used PIs.

Summary: Darunavir represents an important addition to our antiretroviral armamentarium. It is active in vivo in patients who have PI-resistant virus, and preliminary cross-resistance data suggest that darunavir may retain utility in patients who develop virologic failure on tipranavir. However, despite the promising in vitro data, it should be noted that in the patients who had more than 7 substitutions in protease at baseline, only 14% of darunavir-treated patients sustained HIV RNA levels of < 50 copies/mL at week 24. This emphasizes the importance of drug resistance testing prior to treating a patient with darunavir, aggressive construction of an optimized background regimen and, by extrapolation from studies of tipranavir, strong consideration to including enfuvirtide in the regimen. Darunavir's precise role in salvage therapy awaits further controlled trials, including head to head comparisons with tipranavir. The safety profile of darunavir/ritonavir is acceptable, and appears better tolerated than tipranavir/ritonavir, particularly with regard to hepatotoxicity.


  1. FDA-Prezista Approval Letter. www.fda.gov
  2. Tibotec-Prezista Prescribing Information, June 2006. http://www.prezista.com