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JAC Journal of Antimicrobial Chemotherapy (2004) 54, 498–502 DOI: 10.1093/jac/dkh357 Advance Access publication 14 July 2004 Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen Adil Isaac1*, Stephen Taylor1, Patricia Cane2,3, Erasmus Smit2, Sarah E. Gibbons4, David J. White1, Susan M. Drake1, Saye Khoo4 and David J. Back4 1 Received 22 December 2003; returned 3 February 2003; revised 21 March 2004; accepted 2 June 2004 Objectives: To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir. Methods: Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir. Results: At baseline: lopinavir parameters (n 5 10) in BP were within expected levels. Median lopinavir trough concentrations (n 5 5) in CSF and SP were below the limit of detection (BLD) (i.e. < 10 ng/mL) and 248 ng/mL (range 96 –2777), respectively. After indinavir: lopinavir Cmax, Cmin and AUC0 – 12 increased by 9%, 46% and 20%, respectively (P < 0.32, P < 0.32 and P < 0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20–2734). Median indinavir PK parameters were Cmax 3365 ng/mL (range 2130–5194), Cmin 293 ng/mL (14–766), Tmax 2.25 h (1 –3), AUC0 – 12 22452 ng/mL·h (11243 –33661), and t1/2 2.8 h (1.4 –3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21– 86) and 592 ng/mL (96–983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir. Conclusions: Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were > 80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected. Keywords: sanctuary sites, double boosted, protease inhibitors, drug interactions, HIV Introduction Protease inhibitors (PIs) are valuable antiretroviral drugs with proven efficacy in HIV-1-infected patients.1 However, most PIs have unfavourable pharmacokinetic (PK) profiles, which have resulted in complex regimens with frequent dosing, inconvenient dosing schedules and a large number of pills and dietary restric- tions. Adding a sub-therapeutic dose of ritonavir to PIs, and hence boosting PI levels, has largely overcome these problems.2 Combination therapy including two PIs each boosted by a small dose of ritonavir (double boosted PIs) may be an option for drug-experienced patients. However, unexpected drug interactions can lead to toxicities or low drug levels such as the interaction seen between lopinavir and amprenavir.3 .......................................................................................................................................................................................................................................................................................................................................................................................................................... *Corresponding author. Tel: +44-787-678-1398; Fax: +44-1227-783-074; E-mail: [email protected] .......................................................................................................................................................................................................................................................................................................................................................................................................................... 498 JAC vol.54 no.2 q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on February 28, 2014 Hawthorne House, Department of Genitourinary Medicine, Birmingham Heartlands Hospital, Birmingham B9 5SS; 2Health Protection Agency, Birmingham Heartlands Hospital, Birmingham, Birmingham; 3 Antiviral Susceptibility Reference Unit, University of Birmingham, Birmingham; 4Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK Lopinavir and indinavir concentrations in plasma, CSF and semen Table 1. Patient demographics and time on indinavir Person Age (years) 1 2 3 4 5 6 7 8 9 10 54 46 47 38 36 58 38 55 37 57 Median 46.5 Co-administered ART d4T/3TC 3TC/TDF NVP/ddI AZT/ddI NVP/3TC AZT/ddI NVP/AZT AZT/3TC ddI/d4T ABC/ddI Time on indinavir (days) 20 21 13 13 14 14 14 10 NA NA 14 ART, antiretroviral therapy; ABC, abacavir; AZT, zidovudine; d4T, stavudine; ddI, didanosine; NVP, nevirapine; 3TC, lamivudine; TDF, tenofovir. Study design ritonavir/indinavir combinations were taken with food (fat content ± 15 g, 320 kcal); additional fluid intake was recommended. On study visit 2 the same PK and other sampling was as described above; then indinavir was stopped. Participants filled in tolerability questionnaires at both study visits. Heparinized tubes (5 mL) were used to obtain blood for PK samples, which were then processed within 4 h of production. CSF and semen samples were obtained in sterile wide-rimmed tubes after accurate documentation of the times of drug ingestion. Blood and semen were spun at 3000g for 10 min to separate plasma and cell fractions. Samples were then frozen at 708C until analysis. The study was designed as an observational PK study, and pilot study of antiviral activity within the CSF and semen. Pharmacokinetic analysis Materials and methods Patients Ten HIV-1-positive men were enrolled prospectively from Birmingham Heartlands Hospital, UK to participate in the pharmacokinetic study of indinavir 400 mg and lopinavir/ritonavir 400/100 mg in blood plasma (BP), CSF and semen plasma (SP). Local ethics committee approval and informed written consent were obtained for the study. Eligible participants had to meet the following criteria: age >18 years, documented HIV-1 infection and on stable ongoing antiretroviral therapy containing lopinavir/ritonavir (Table 1). All 10 participants also took combinations of nucleoside analogues, and three took nevirapine as part of their combination. Participants were advised to take lopinavir/ritonavir doses strictly 12 h apart for 2 weeks before study visit 1. Drug administration and sampling On study visit 1 each participant attended 2 h before their usual morning medication dose, and provided semen by masturbation and/or underwent a lumbar puncture for CSF sampling. Blood was sampled by insertion of a venous cannula and drawn into a heparinized tube at 0 h and then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 10, 12 h after an observed dose of drug. Also, all participants underwent HIV RNA virus load, CD4 and blood chemistry (liver and kidney function tests, triglyceride and cholesterol levels) measurements. They were instructed to add indinavir 400 mg to their stable regimens and attend a second PK study day 2 weeks later. Lopinavir/ An HPLC/MS/MS system, with a lower level of detection of 10 ng/mL, was used to measure drug levels in BP, CSF and SP.12 Lopinavir and indinavir drug concentrations were evaluated for maximum concentration (Cmax), time to peak (Tmax) and the area under the curve to 12 h (AUC0 – 12), and elimination half-life (t1/2) values were determined by non-compartmental analysis using TOPFIT computer software (Gustav Fischer Verlag, Stuttgart, Germany). The elimination rate constant lz was calculated by log-linear regression of the terminal portion of the plasma drug concentration – time curve using the least squares method. The terminal elimination half-life (t1/2,z) was calculated from ln 2/lz. The area under the drug – time curve was determined by the log-linear trapezoid rule. HIV RNA determinations Blood plasma viral load (BPVL) was determined by the Roche Ultrasensitive assay (Brachburg, NJ, USA) as per the manufacturer’s instructions. CSF viral load and semen plasma viral load (SPVL) were determined by NASBA Nuclisens. The lower limit of quantification was 50 copies/mL for BP and 400 copies/mL for CSF and semen. The latter was 400 copies due to the small volume of CSF and semen analysed (1 mL). Statistical analysis The Wilcoxon matched pairs signed rank test was used to compare PK and other parameters. 499 Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on February 28, 2014 Both indinavir and lopinavir/ritonavir are metabolized by cytochrome P450 (CYP3A4) isoenzyme; indinavir, lopinavir and ritonavir are inhibitors of CYP3A4, and therefore co-administration of these drugs can lead to significant drug interactions. Nonetheless, favourable pharmacokinetics have been demonstrated in combinations including lopinavir/ritonavir and indinavir 600 mg twice daily.4 Twice-daily indinavir 400 mg boosted with a small dose of ritonavir of 100 mg was shown in a recently published pilot study5 to be efficacious and well tolerated; this is most likely due to higher drug exposure coupled with low indinavir Cmax. In contrast, twice-daily regimens containing higher doses of indinavir/ritonavir were not so well tolerated despite virological effectiveness.6,7 Recent studies have suggested that lopinavir penetrates poorly into the CSF and male genital tract.8,9 Hence these viral reservoirs may be potential sites for ongoing viral replication in the face of a suppressed plasma viral load. In contrast, studies with indinavir have demonstrated good penetration of this drug into these anatomical sites with good antiviral activity.10,11 The rationale for this study is two-fold. First, to obtain PK data, as they are not available from the manufacturers, to evaluate the feasibility of combining twice-daily indinavir 400 mg and lopinavir/ritonavir 400/100 mg, utilizing the low-dose ritonavir that is co-formulated with lopinavir. Secondly, to evaluate indinavir and lopinavir penetration and antiviral activity in the CSF and semen, when these drugs are co-administered. A. Isaac et al. Table 2. Summary of lopinavir and indinavir parameters in blood plasma Day 2 Parameter Cmax (ng/mL), range Cmin (ng/mL), range AUC0 – 12 (ng/mL·h), range Day 1 LPV (n = 10) LPV (n = 8) IDV (n = 8) 11449 8179– 17407 4811 1168– 10945 104414 14387 8668– 19552 5612 1181– 13255 114845 3365 2130– 5194 293 14 –766 22452 52502– 169106 58163– 203960 11243– 33661 LPV, lopinavir; IDV, indinavir. Day 1, at baseline; Day 2, after indinavir was added. Patient characteristics Ten men were enrolled between September 2002 and June 2003. Their median age was 46.5 years (range, 36– 58), median CD4 381 cells/mm3 (range, 96 –774) and HIV-1 RNA VL <50 copies/mL in 80% of patients. Seven patients were on at least their second, and two were on their first, PI-containing regimen. Lopinavir pharmacokinetics Ten men provided BP for 0–12 h PK determinations. Five patients provided CSF and SP samples. Table 2 shows the median BP lopinavir PK parameters. All patients had undetectable (i.e. <10 ng/mL) lopinavir concentrations in CSF. Median SP lopinavir concentrations were 248 ng/mL (range 96 –2777). Eight men provided blood samples for the second 0–12 h study. Four patients provided CSF and four provided semen. The median PK parameters for lopinavir when co-dosed with indinavir are shown in Table 2. Median (range) lopinavir t1/2 and Tmax were 11.6 h (3.1 –21.5) and 2.7 h (1.5 –4). Two of four men had lopinavir concentrations in CSF detectable at 27 and 29 ng/mL, respectively. The median SP lopinavir concentration was 655 ng/mL (20–2734). Post-indinavir the median increase from baseline for lopinavir Cmax, Cmin and AUC0 – 12 was +9% (range 23% to +78%), +46% ( 68% to +130%) and +20% ( 36% to +102%), respectively. None of these was statistically significant, P < 0.32, 0.32 and 0.2 (see Figure 1). Indinavir pharmacokinetics Table 2 and Figure 2 show indinavir PK parameters in BP. Median indinavir (range) t1/2 and Tmax were 2.8 h (1.4 –3.7) and 2.25 h (1 –3). Median indinavir CSF and SP concentrations were 39 ng/mL (21–86) and 592 ng/mL (96 –983). Pharmacodynamic data Viral load data: in two of eight men with detectable BPVL of 310 and 200 copies/mL, viral load became below the limit of detection (BLD) (<50 copies/mL) after addition of indinavir. In two of Figure 2. Pharmacokinetic parameters of indinavir 400 mg twice daily in blood plasma (filled diamonds) when dosed with twice-daily lopinavir/ ritonavir 400/100 mg. The broken line is the target trough indinavir concentration for wild-type virus. four men with low-level viraemia in SP (BPVL BLD), at 779 and 970 copies/mL, viral load became BLD (<400 copies/mL) postindinavir.12 All subjects had VL BLD (<400 copies/mL) pre- and postindinavir in the CSF. No significant changes in CD4 counts or blood chemistry post-indinavir were noted. Tolerability The lopinavir/ritonavir/indinavir combination was well tolerated. There were no differences in adverse events before and after adding indinavir. The main side effect was mild to moderate diarrhoea (30%). However, no patient stopped indinavir before the end of the study, but two withdrew their consent from the second arm of the study due to headaches from the lumbar puncture. Discussion To our knowledge, these are the first data on the pharmacokinetics and tolerability of lopinavir/ritonavir and indinavir 500 Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on February 28, 2014 Results Figure 1. Pharmacokinetic parameters of lopinavir in blood plasma at baseline (filled triangles), and after addition of indinavir (filled squares). The broken line is the target trough lopinavir concentration for wild-type virus. Lopinavir and indinavir concentrations in plasma, CSF and semen showed excellent tolerability throughout the study duration (2 weeks); and there were no significant changes from baseline in CD4 counts, blood chemistry or lipids. Also, participants stated that they would take this combination again if offered to them. Our results suggest that indinavir 400 mg and lopinavir/ritonavir 400/100 mg twice daily is a promising, convenient and welltolerated regimen. However, larger efficacy trials, including both treatment-naive and -experienced patients, are needed to confirm these results, and ascertain whether the favourable PK profile will translate into clinical benefit. Acknowledgements We thank all patients and staff involved with this study. This study was partially supported by a West Midlands NHSE Research grant to S.T. and was not funded by a pharmaceutical company. References 1. Hammer, S. M., Squires, K. E., Hughes, M. D. et al. (1997). A controlled trial of two nucleoside analogues plus IDV in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. New England Journal of Medicine 337, 725– 39. 2. James, J. S. (1996). Ritonavir and saquinavir combination: 12week data at ICAAC. AIDS Treatment News 256, 3.3. 3. Mauss, S., Schmutz, G., Kuschak, D. et al. (2002). Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir. AIDS 16, 296– 7. 4. Harris, M., Alexander, C., Ting, L. et al. (2002). Rescue therapy with indinavir 600 mg twice daily and lopinavir/ritonavir. In Program and Abstracts of the Sixth International Congress on Drug Therapy in HIV Infection, Glasgow, 2002. Abstract P170. 5. Ghosn, J., Lamotte, C., Ait-Mohand, H. et al. (2003). Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients. AIDS 17, 209– 14. 6. Rockstroh, J. K., Bergmann, F., Wiesel, W. et al. (2000). Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. AIDS 14, 1181–5. 7. Cahn, P., Casiro, A., Puentes, T. et al. (2001). Continued indinavir (800 mg tid) versus switching to indinavir+ritonavir (800/100 mg bid) in HIV patients having achieved viral load suppression. A randomised study: the bid efficacy and safety trial. In Program and Abstracts of the First IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, 2001. Abstract 60. 8. Lafeuillade, A., Solas, C., Halfon, P. et al. (2002). Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations. HIV Clinical Trials 3, 27–35. 9. Sankatsing, S., Droste, J., Burger, D. et al. (2002). Limited penetration of lopinavir into seminal plasma of HIV-1-infected men. AIDS 16, 1698–700. 10. Van Praag, R. M., Weverling, G. J., Portegies, P. et al. (2000). Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS 14, 1187– 94. 11. Taylor, S., Back, D. J., Drake, S. M. et al. (2001). Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir. Journal of Antimicrobial Chemotherapy 48, 351–4. 12. Reynolds, H. E., Tjia, J. F., Gibbons, S. E. et al. (2001). Simultaneous determination of four HIV protease inhibitors by HPLCMS/MS for use in therapeutic drug monitoring service. British Journal of Clinical Pharmacology 52, 481P– 482P. 13. Abbott Laboratories Ltd. Kaletra summary of product characteristics. March 2001. 501 Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on February 28, 2014 400 mg. By combining these drugs, we have demonstrated: therapeutic drug concentrations of both lopinavir and indinavir in blood plasma, the lack of negative drug–drug interactions, good tolerability, and the added benefit of drug penetration into CSF and semen. We have shown that the pharmacokinetics of lopinavir when combined with indinavir were within the expected ranges.13 Unlike the case of lopinavir and amprenavir, no negative drug – drug interactions took place.3 However, there was a trend toward increased lopinavir parameters, which did not reach statistical significance Our study confirmed previous reports that, unlike indinavir, lopinavir penetrates poorly into the CSF and semen;8,13 interestingly, two patients had lopinavir concentrations in CSF of 27 and 29 ng/mL, which are above both the limits of detection (10 ng/mL) and the non-protein-corrected EC50 of lopinavir, after the addition of indinavir. Together with the upward trend in lopinavir BP concentrations, these results suggest that indinavir probably exerts some added inhibition of lopinavir metabolism. Several groups have reported previously that ritonavir, at various doses, improves indinavir pharmacokinetics compared with the standard indinavir 800 mg three times daily dose. Investigated doses have included indinavir/ritonavir 400/400, 800/100, 600/100 and 400/100 mg. However, the former two were poorly tolerated unlike 600/100 and 400/100 mg.6,7 Combined with lopinavir, indinavir 600 mg was shown to have favourable pharmacokinetics and tolerability in both healthy volunteers and HIV-1-positive individuals.4,14 Our results showed: a two-fold decrease in indinavir Cmax; a two-fold increase in Cmin; and a similar AUC compared with the licensed dose of indinavir of 800 mg three times daily.15 While confounding, due to nevirapine taken by three patients, could not be ruled out, these results are comparable to published data on singleboosted indinavir/ritonavir 400/100 mg. In addition, a comparison between our data and indinavir 600 mg (historical data) revealed no significant difference in indinavir parameters (M. Harris, personal communication). Consistent with previous reports, indinavir concentrations in CSF and semen were above the non-protein-corrected IC50 values of 21 ng/mL and 100 ng/mL, respectively, in all samples collected. These results confirmed our hypothesis that the lopinavir/ritonavir/indinavir combination may result in levels above the threshold concentration in CSF and semen and, therefore, may control viraemia in these sites, which are virtually closed to lopinavir/ritonavir alone. This is due to the high protein binding of lopinavir and hence its small volume of distribution. Nevertheless, as all patients in this study were taking HAART regimens containing nucleoside and non-nucleoside reverse transcriptase inhibitors, some of which have good penetration into such sites, detectable viraemia was found in only a small minority in semen and in none in the CSF. Two patients had BP viraemia that became BLD after the addition of indinavir; despite the small numbers, this suggests that indinavir might be a useful add-on to failing regimens containing lopinavir/ritonavir. Moreover, two other patients had detectable viraemia in the SP with BPVL BLD (<50 copies/mL), which became undetectable (<400 copies/mL) after indinavir was added, confirming that indinavir may be useful in controlling HIV in semen. In contrast to previously reported double boosted combinations such as lopinavir/ritonavir and saquinavir soft gel,16 our results A. Isaac et al. 14. Bertz, R. J., Foit, C., Ashbrenner, E. et al. (2002). Assessment of steady-state pharmacokinetic interaction of lopinavir/ritonavir with either indinavir or saquinavir in healthy subjects. In Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Abstract A-1822, p. 26. American Society for Microbiology, Washington, DC, USA. 15. Merck Sharp and Dohme. Crixivan Prescribing Information. September 2001. 16. Ribera, E., Diaz, M., Poul, L. et al. (2002). Steady state pharmacokinetics of double boosted regimens of lopinavir, plus saquinavir soft in HIV-infected patients. In Program and Abstracts of the Fourteenth International AIDS Conference, Barcelona, 2002. Abstract TuPeB4545. 17. Acosta, E. & Gerber, J. G. (2002). Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Research and Human Retroviruses 18, 825 –34. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on February 28, 2014 502