To the Editor:
The introduction of inexpensive generic copies of antiretrovirals in resource-limited settings has the potential to provide access to treatment for millions of HIV-infected individuals.1 The generic antiretrovirals are expected to provide the same efficacy and safety as demonstrated for brand-name products; however, assurance of bioequivalence to brand formulations is also required. In this context, studies demonstrating comparable bioavailability of generic versions of antiretroviral drugs are of paramount importance to avoid the risk of substandard antiretroviral therapy.2 In Argentina, generic protease inhibitors are currently available to 16,000 HIV-infected individuals through the Ministry of Health. In this open-label crossover study, we compare systemic exposure of a generic formulation of indinavir (IDV) (Inhibisam; Laboratorio Richmond, Buenos Aires, Argentina) with brand IDV (Crixivan; Merck & Co., Whitehouse Station, NJ) in the context of ritonavir (RTV)-boosted therapy.
The study included 10 adult patients (median age = 33 years, interquartile ratio [IQR]: 29-55 years) in Buenos Aires, Argentina (9 men, 1 woman), who were on their first highly active antiretroviral therapy (HAART) regimen, including twice-daily IDV/RTV (800/100 mg), and remained virologically suppressed (<50 copies/mL) for a minimum of 24 weeks. The median baseline plasma HIV-RNA level was 5.27 log (IQR: 4.69-5.87 log), and the median CD4 count at study entry was 298 cells/μL (IQR: 70-536 cells/μL). In general, liver function was normal in these patients (median aspartate aminotransferase [AST] = 24.5 U/L, IQR: 22-27.8 U/L; median alanine aminotransferase [ALT] = 19 U/L, IQR: 16.5-34.5 U/L). Backbone double nucleosides included combinations of zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), stavudine (d4T), and abacavir (ABV) at regular dosing intervals. One patient's IDV/RTV dose was supplemented with ABC and nevirapine. Another patient was also being treated with trimethoprim-sulfamethoxazole (Septra) and fluconazole at the time of both tests.
The average exposure of the 2 formulations was tested using a nonreplicated crossover design with each subject serving as his/her own control. Six of 10 volunteers were sequenced from Inhibisam to Crixivan, whereas the remaining 4 were sequenced from Crixivan to Inhibisam. Blood samples were taken immediately before the morning dose of IDV/RTV and then at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the dose was administered. Patients were reassessed in the same way approximately 14 days later after switching formulations. IDV/RTV doses were administered in a fasted state on the day of pharmacokinetic (PK) assessment. Adherence was monitored by pill count.
Plasma IDV concentrations were determined by a validated assay using reverse phase high-pressure liquid chromatography coupled with tandem mass spectroscopy. The upper and lower limits of quantification for IDV were 79 ng/mL and 11,800 ng/mL, respectively. Average peak, trough, and area under the curve for 0 to 12 hours (AUC0-12h) for the 2 formulations were compared using a paired t test. The peak concentration was taken as the highest observed concentration (Cmax), trough concentration was selected at 12 hours after the dose was administered (C12h), and the AUC0-12h was determined using the linear trapezoid rule.
On average, IDV exposures were slightly greater for the generic formulation (Fig. 1); however, this was not statistically significant. No sequencing bias was detected. Generally, IDV exposures were within the therapeutic limits, although 1 patient exhibited a C12h below the recommended minimum of 100 ng/mL while taking Inhibisam. Similarly, 1 and 3 patients exceeded the maximum recommended Cmax of 10,000 ng/mL while taking Crixivan and Inhibisam, respectively. After completion of the study, all patients continued on the generic formulation. Plasma HIV RNA levels remained less than 50 copies/mL at a median follow-up interval of 12 weeks in all patients. There were no serious laboratory abnormalities or clinical adverse events after switching IDV formulations.
Although our results suggest that Inhibisam should provide suppression of viral replication similar to that obtained with Crixivan, selection of this study sample within a cohort of “virologic responders” may bias this assumption. At least for patients who achieve virologic success, Inhibisam seems to be a suitable substitute for Crixivan. C12h values, which strongly correlate with the antiviral activity of IDV,3-5 were higher than the recommended lower limits in 90% of cases in which Inhibisam was used. Furthermore, the mean C12h values of 1007 ng/mL and 1383 ng/mL found in this study for Crixivan and Inhibisam, respectively, compare favorably with IDV C12h values reported previously for IDV/RTV at a dose of 800/100 mg administered twice daily.6-8
Of concern in this study was the number of patients presenting with IDV Cmax values in excess of the recommended safe limit. Notably, 3 patients presented with IDV Cmax values greater than 10,000 ng/mL while taking Inhibisam, as did 1 patient while taking Crixivan. Thus, 40% of the patients in this study were at increased risk of nephrotoxicity7,9 based on pharmacokinetic data collected within a period of less than 1 month. This highlights the necessity of impressing on patients the importance of proper hydration while taking IDV/RTV.10
Generic antiretroviral drugs are increasingly used in resource-limited settings.11,12 Thousands of HIV-infected patients from Latin America are currently exposed to generic versions of protease inhibitors, including IDV. Although concern has been raised about the safety and effectiveness of generic substitutes in developing countries, little information is available about the pharmacokinetic properties of these formulations. This is the first independent evaluation of the pharmacokinetics of a generic protease inhibitor in Argentina. In this series of patients on stable antiretroviral therapy, we provide evidence that Inhibisam matched pharmacokinetic exposures to Crixivan, at least in the context of RTV boosting. Further work is warranted to expand pharmacokinetic evaluations where generic antiretrovirals are widely available to treat HIV-infected individuals.
Carlos Zala, MD*
Christopher S. Alexander, PhD†
Claudia Ochoa, MD*
Silvia Guillemi, MD†
Lillian S. Ting, BSc†
Simon Bonner, MSc†
Pedro Cahn, MD, PhD*
P. Richard Harrigan, PhD†
Julio S. G. Montaner, MD, FRCPC†
*Fundación Huesped Buenos Aires, Argentina; and †British Columbia Centre for Excellence in HIV/AIDS Vancouver, British Columbia Canada
1. Angerer T, Wilson D, Ford N, et al. Access and activism: the ethics of providing antiretroviral therapy in developing countries. AIDS
. 2001;15(Suppl 5):S81-S90.
2. Henney JE. Review of generic bioequivalence studies. JAMA
3. Burger D, Hugen P, Reiss P, et al, for the ATHENA Cohort Study Group. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS
4. Fletcher CV, Anderson PL, Kakuda TN, et al. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS
5. Murphy RL, Sommadossi JP, Lamson M, et al. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J Infect Dis
6. van Heeswijk RPG, Veldkamp AI, Hoetelmans RMW, et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals. AIDS
7. Burger D, Boyd M, Duncombe C, et al. Pharmacokinetics and pharmacodynamics of indinavir with or without low-dose ritonavir in HIV-infected Thai patients. J Antimicrob Chemother
8. Burger DM, Hugen PW, Aarnoutse RE, et al. A retrospective, cohort based survey of patients using twice-daily indinavir plus ritonavir combinations: pharmacokinetics, safety and efficacy. J Acquir Immune Defic Syndr
9. Aarnoutse RE, Wasmuth JC, Fatkenheuer G, et al. Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir. Antivir Ther
10. Crixivan® Product Monograph. Whitehouse Station, NJ: Merck & Co.; 1996, 1997, 1998, 1999.
11. Coetzee D, Hildebrand K, Boulle A, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS
12. Kumarasamy N, Solomon S, Chaguturu SK, et al. The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India. AIDS