Low-doses of indinavir boosted with ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and tolerability

Tim R. Cressey1,2,*, Prattana Leenasirimakul3, Gonzague Jourdain1,2, Michel Tod4, Pra-ornsuda Sukrakanchana2, Suparat Kunkeaw2, Chutima Puttimit2 and Marc Lallemant1,5

1 Harvard School of Public Health, Harvard University, Boston, MA, USA; 2 IRD 054 – Program for HIV Prevention and Treatment, Chiang Mai, Thailand; 3 Nakornping Provincial Hospital, Chiang Mai, Thailand; 4 Pharmacie-toxicologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, France; 5 Institut de Recherche pour le Développement (IRD), UR 054, Paris, France


* Corresponding author. Present address. PO Box 207, Prasing Post, Muang, Chiang Mai, 50205, Thailand. Tel: +66-5381-4270; Fax: +66-5381-4269; Email: tim{at}phpt.org

Received 4 January 2005; returned 5 March 2005; revised 21 March 2005; accepted 2 April 2005


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: To assess the steady-state pharmacokinetics of two reduced doses of indinavir boosted with ritonavir (indinavir/ritonavir) in HIV-infected Thai patients.

Patients and methods: Thirteen immunocompromised antiretroviral-naive patients (6 males, 7 females) initiated 600/100 mg indinavir/ritonavir, zidovudine and lamivudine, every 12 h. After 1 month, blood samples were taken at pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h after drug intake. Indinavir dosing was then reduced to 400 mg (twice daily) and 1 week later an identical series of samples were drawn. Patients then resumed 600 mg of indinavir. HIV-1 RNA viral load was determined at 8, 24 and 48 weeks. Indinavir plasma levels were determined by HPLC and pharmacokinetic parameters by non-compartmental analysis.

Results: Median (range) weight was 58 kg (51–73) for men and 53 kg (46–59) for women. On 600 mg of indinavir, median indinavir AUC, Cmax, and Cmin were 39.3 mg·h/L (20.6–50.5), 6.2 mg/L (3.7–9.0) and 0.41 mg/L (0.12–0.77), respectively, and on indinavir 400 mg, 18.3 mg·h/L (11.1–33.0), 3.8 mg/L (2.2–7.8) and 0.17 mg/L (0.10–0.39), respectively. No renal complications were observed. At 48 weeks, 6/13 (46%) patients had stopped 600 mg of indinavir due to intolerability (gastrointestinal and cutaneous), and 5/7 (71%) patients had a HIV-1 viral load <50 copies/mL.

Conclusions: Reduced doses of indinavir/ritonavir maintained adequate indinavir plasma levels compared to current guidelines suggesting that these doses are efficacious in this setting. Considering the poor tolerability of 600 mg of indinavir, the 400 mg of indinavir may be preferred due to its lower exposure indices but long-term efficacy data are needed.

Keywords: HIV , pharmacology , highly active antiretroviral therapy , HAART , Thailand


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
To date, the combination of indinavir boosted with ritonavir (indinavir/ritonavir) is the least expensive protease inhibitor-based highly active antiretroviral therapy (HAART) regimen in Thailand and in several other resource-limited settings. In 2004, the 800/100 mg indinavir/ritonavir dose, every 12 h, was recommended in the National Thai Guidelines for antiretroviral treatment,1 and this dosing is based on clinical data collected in western countries. The average adult size/weight in Thailand is smaller than in western populations and genetic differences, which may or may not be influenced by ethnicity, may contribute to pharmacokinetic variability. Therefore, using dosing recommendations derived from US and European studies in the Thai population may lead to more severe side effects due to comparatively higher drug levels, which in turn may lower compliance and lead to treatment failures. Indeed, in the international 2NN study, a slightly higher rate of antiretroviral drug-associated adverse events was reported in Thai patients than in non-Asian populations,2 and lower drug clearance in these patients has been reported.3

In a study comparing indinavir/ritonavir (800 mg/100 mg, twice daily) and indinavir alone (800 mg, three times daily), performed in Thailand, it was reported that after 112 weeks of therapy slightly more adverse events, such as clinical nephrolithiasis, drug interruptions and hyperlipidaemia occurred in the twice-daily arm.4 Recently, the indinavir pharmacokinetics of indinavir/ritonavir (800/100 mg, twice daily) in Thai patients were found to be similar to those observed in Caucasian patients,5 with the exception that a higher maximum plasma drug concentration (Cmax) was observed in Thai patients.

Considering that the optimal indinavir/ritonavir dose needed to be determined for Thai patients, a study was conducted to compare the pharmacokinetics of two reduced indinavir/ritonavir doses (600/100 mg versus 400/100 mg) in the same subjects with recommended plasma drug levels. Efficacy and tolerability data were also collected up to 48 weeks in these patients.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population

The study enrolled immunocompromised antiretroviral-naive, HIV-infected Thai patients attending routine clinic visits at Nakornping Hospital, Chiang Mai, after they had provided written informed consent. We excluded patients with concomitant treatments that could interfere with the pharmacokinetics of indinavir such as rifampicin, rifapentine, fluconazole, itraconazole, St John's Wort (Hypericum perforatum), or patients with regular consumption of grapefruit juice. The patients initiated indinavir (600 mg) boosted with ritonavir (100 mg), in combination with zidovudine (300 mg for >60 kg and 200 mg for <60 kg) and lamivudine (150 mg), all every 12 h. Prior to initiating antiretroviral therapy, all patients received counselling on antiretroviral drugs, with specific advice to take additional fluids to reduce the risk of nephrolithiasis associated with indinavir and to take all their drugs immediately after their morning and evening meals. Only one patient had no access to a refrigerator, and stored ritonavir at room temperature for a maximum of 30 days. Adherence was assessed by exact pill count. This study was approved by the Ethics Committee at the Faculty of Associated Medical Sciences, Chiang Mai University.

Pharmacokinetic, design, analysis and statistics

After 1 month of treatment, patients were admitted to the hospital in the evening for 24 h to determine the steady-state pharmacokinetics of indinavir and ritonavir (600/100 mg indinavir/ritonavir). After their evening meal, patients took all their drugs and remained in the hospital overnight. The following morning, patients had breakfast and then blood samples were taken at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h after drug intake. After blood sampling was completed, the dose of indinavir was reduced to 400 mg. One week later, the patients returned to the hospital and a second series of blood samples, identical with the previous week's sampling, were drawn to assess the pharmacokinetics of the 400/100 mg indinavir/ ritonavir dose. Patients then resumed the 600 mg indinavir dosage because real-time monitoring of plasma drug levels was not available at that time. All blood samples were centrifuged, the plasma removed, aliquoted and frozen within 1 h. Samples were stored at –20°C. Indinavir and ritonavir plasma drug concentrations were measured by high performance liquid chromatography (HPLC)6 at the Faculty of Associated Medical Sciences, Chiang Mai University. This method was re-validated in the laboratory in Chiang Mai with an inter- and intra-assay variability of CV (coefficient of variation) <5% at three levels of the calibration curve. The lower limit of assay quantification (LLOQ) was 50 ng/mL. The laboratory participates in two international external quality control (QC) programmes: the AIDS Clinical Trial Group (ACTG), USA, Pharmacology Quality Control (Precision Testing) program, and ASQUALAB Quality Control program, France, and has successfully passed for all drugs. Data were analysed with WinNonLin (Version 4.1, Pharsight, USA) using non-compartment methods. The following parameters were calculated: maximum observed concentration (Cmax, mg/L), observed time to maximum concentration (Tmax, h), minimum observed concentration (Cmin, mg/L). Area under the curve (AUC, 0–12 h, mg·h/L) was calculated using the trapezoidal rule. Continuous variables were compared between sexes using a Mann–Whitney U-test. Pharmacokinetics parameters were compared between the two doses using a Wilcoxon signed-rank test. All statistical tests were carried out using Stata version 8.0 for Windows Stata Corporation, TX, USA).

Measurement of plasma HIV-1 RNA

Plasma HIV-1 RNA levels were assessed according to the standard protocol (limit of detection, 400 copies/mL) or the ultrasensitive protocol (limit of detection, 50 copies/mL) of the Cobas Amplicor HIV-1 Monitor kit (version 1.5, Roche Molecular Systems).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Thirteen patients were enrolled. Median (range) age was 35 years (29–41); weight was 58 kg (51–73) for men and 53 kg (46–59) for women, CD4 count 166 cells/mm3 (52–268), HIV-1 RNA 10 715 copies/mL (725–389 000), serum glutamic pyruvic transaminase (SGPT) 38 U/L (26–69) and creatinine 0.9 mg/dL (0.7–1.2). SGPT and creatinine levels were lower in women compared with men (P =0.03 and P =0.01, respectively) but no differences were observed in weight, CD4 cell count or viral load.

Eleven patients (six men and five women) had pharmacokinetics evaluations at both indinavir/ritonavir doses (Table 1). Significantly higher indinavir AUC, Cmax, and Cmin were observed at the 600/100 mg indinavir/ritonavir dose compared with the 400/100 mg indinavir/ritonavir dose. At the 600/100 mg indinavir/ritonavir dose, median AUC0–12 (28.2 mg·h/L, range 20.6–41.2) and Cmax (5.2 mg/L, range 3.4–6.9) were significantly higher in women compared with men (41.5 mg·h/L, range 39.8–51.7 and 6.9, range 5.5–8.0, respectively) (P=0.02 and P=0.05, respectively). At the 400/100 mg indinavir/ritonavir dose, no significant differences were observed in indinavir pharmacokinetic parameters between men and women.


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Table 1. Summary of the pharmacokinetic parameters of indinavir (IDV) and ritonavir (RTV) at two reduced IDV doses combined with RTV (600/100 and 400/100 mg) as part of highly active antiretroviral therapy in HIV-infected Thai patients

 
No serious adverse events were reported. Adherence was greater than 95% for all patients. Two women on 600/100 mg indinavir/ritonavir dose withdrew after 7 and 20 days of treatment, respectively, due to mild nausea and vomiting (one of these patients also experienced dry skin and lips, and mild heart palpitations). A male patient withdrew while on 600/100 mg indinavir/ritonavir dose after 12 weeks due to mild nausea and vomiting. These three patients who withdrew were all switched to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen. After ~40 weeks, a further three female patients on 600/100 mg indinavir/ritonavir dose reported side effects, in particular alopecia, however the symptoms resolved after the indinavir/ritonavir dose was reduced to 400/100 mg. No nephrotoxicity was reported.

In total, 11/13, 10/13 and 7/13 patients remained on 600/100 mg indinavir/ritonavir for 8, 24 and 48 weeks, respectively. All patients on 600/100 mg indinavir/ritonavir maintained their viral load <400 copies/mL from 8 to 48 weeks and 71% had a viral load <50 copies/mL at 48 weeks (Table 2). The three patients who were switched to the lower 400/100 mg indinavir/ritonavir dose after 40 weeks due to toxicity maintained their viral load <50 copies/mL at 48 weeks. The median CD4 increase was 122 cells/mm3 (range 64–498) at 48 weeks in patients who remained on an indinavir/ritonavir-based regimen (n =10).


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Table 2. HIV-1 RNA plasma viral loads (VL) and CD4 cell counts at baseline and after 8, 24 and 48 weeks of treatment with 600/100 mg indinavir/ritonavir twice daily

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, two reduced doses of indinavir boosted with ritonavir (600/100 mg and 400/100 mg) in antiretroviral-naive patients as part of a HAART regimen produced adequate indinavir plasma levels, i.e. maintained indinavir levels above 100 ng/mL,7 which is recommended by the current guidelines.8,9

All patients on 600/100 mg of indinavir/ritonavir, as well as those who were switched to a reduced dosing (indinavir 400 mg) due to intolerance, achieved optimal virological suppression (at the threshold of 50 copies/mL) at 48 weeks. This confirmed that the drug levels obtained with this regimen were efficacious in these patients. It is noticeable that no nephrotoxicity was reported in this study although such toxicity has been reported as a very frequent adverse event at the higher 800/100 mg indinavir/ritonavir dosing.4 However, the tolerance of the 600/100 mg indinavir/ritonavir dose was poor in these patients with 6/13 unable to tolerate the higher dose, mainly due to upper gastrointestinal symptoms and cutaneous effects.

Interestingly, in this study, five of the six patients who experienced toxicities possibly related to indinavir on indinavir/ritonavir 600/100 mg were female and a significantly higher indinavir exposure (AUC0–12) and Cmax was observed in female patients at this dose. Previously, it has been suggested that female patients are at a higher risk of toxic plasma indinavir concentrations than male patients;10 however, no difference in indinavir exposure between sexes was found at the lower 400/100 mg dose. Based on these observations, it can be suggested that the 600/100 mg indinavir/ritonavir dosage can be too high for some Thai patients, therefore the lower 400/100 mg indinavir/ritonavir dose which also provides adequate plasma drug levels may be preferred. Indeed, in Europe, the pharmacokinetics and efficacy of 400/100 mg of indinavir/ritonavir has been reported in 20 patients who were switched from indinavir three times a day with favourable findings,11 and, more recently, the 400/100 mg dose was shown to be efficacious and safe after 48 weeks in 40 antiretroviral-naive patients.12

In this study, the 400 mg indinavir dose did produce Cmin levels very close to the 100 ng/mL indinavir efficacy threshold, thus the risk of under exposure is probably higher with 400 mg of indinavir than 600 mg, especially given the short half-life of indinavir where there is a risk of subtherapeutic levels in cases of missed or late doses. The use of therapeutic drug monitoring (TDM) of antiretroviral drugs is increasingly becoming integrated into routine clinical care of HIV-infected patients on HAART. A study assessing the benefit of TDM of 400/100 mg of indinavir/ritonavir in this Thai antiretroviral-naive population would be needed to determine whether TDM helps optimize this treatment.

In conclusion, both 600/100 and 400/100 mg of indinavir/ritonavir produced adequate plasma drug levels in Thai patients when compared with recommended levels. However, the 400/100 dose provides lower plasma concentrations, which may be adequate for naive Thai patients, but more data are needed in drug-experienced patients. Suppression of virus replication was observed in all nine patients still on indinavir/ritonavir at 48 weeks follow-up. However, the 600 mg indinavir dose produced high intolerability, particularly in women. In this setting, physicians may elect to initially use the lower reduced indinavir/ritonavir dose (400/100 mg) as its exposure indices may be preferable to prevent intolerability. Long-term efficacy data of 400/100 mg are being collected in similar populations by our group and others; meanwhile close virological and therapeutic-drug monitoring is desirable.


    Acknowledgements
 
We would like to thank the two study nurses Ms Chanannat Chanrin and Ms Rattiya Hangsamsibjed for their contribution. The following reagents were obtained through the NIH AIDS Research and Reference Program, Division of AIDS, NIAID, NIH: indinavir and ritonavir from DAIDS, NIAID, NIH. Also, we would like to acknowledge Abbott Laboratories for providing the experimental material A86093, which was used as an internal standard in the HPLC method to measure indinavir and ritonavir. This work was supported by Institut de Recherche pour le Développement (IRD), UR 054.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . National Guidelines for the Clinical Management of HIV Infection in Children and Adults. AIDS Division, Department of Communicable Disease Control. Ministry of Public Health, Nonthaburi Thailand.

2 . van Leth F, Phanuphak P, Ruxrungtham K et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363: 1253–63.[CrossRef][ISI][Medline]

3 . Kappelhoff BS, van Leth F, MacGregor TR et al. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antivir Ther 2005; 10: 145–55.[Medline]

4 . Boyd M, Duncombe C, Ruxrungtham K et al. Indinavir TID vs indinavir/ritonavir BID in combination with AZT/3TC for HIV infection in nucleoside pretreated patients: HIV-NAT 005 76-week follow up. In: Programs and Abstracts of the Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2002. Abstract 422-W. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.

5 . 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 2003; 51: 1231–8.[Abstract/Free Full Text]

6 . Droste JA, Verweij-Van Wissen CP, Burger DM. Simultaneous determination of the HIV drugs indinavir, amprenavir, saquinavir, ritonavir, lopinavir, nelfinavir, the nelfinavir hydroxymetabolite M8, and nevirapine in human plasma by reversed-phase high-performance liquid chromatography. Ther Drug Monit 2003; 25: 393–9.[CrossRef][ISI][Medline]

7 . Burger DM, Hoetelmans RM, Hugen PW et al. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antivir Ther 1998; 3: 215–20.[ISI][Medline]

8 . Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses 2002; 18: 825–34.[CrossRef][ISI][Medline]

9 . HIVpharmacology.com. Editorial Board for TDM Guidelines: Optimising TDM in HIV Clinical Care. A Practical Guide to Performing Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents. Version 1.0 edn.

10 . Burger DM, Siebers MC, Hugen PW et al. Pharmacokinetic variability caused by gender: do women have higher indinavir exposure than men? J Acquir Immune Defic Syndr 2002; 29: 101–2.[ISI][Medline]

11 . Ghosn J, Lamotte C, Ait-Mohand H et al. Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients. AIDS 2003; 17: 209–14.[CrossRef][ISI][Medline]

12 . Duvivier C, Myrto A, Marcelin AG et al. Efficacy and safety of ritonavir/indinavir 100/400 mg twice daily in combination with two nucleoside analogues in antiretroviral treatment-naive HIV-infected individuals. Antivir Ther 2003; 8: 603–9.[Medline]





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