- Email: [email protected]
Ritonavir Tablets (Lopimune, Cipla) and the abbott brand (Norvir Soft-Gel Capsules and Kaletra Tablets)
GLOBAL HEALTH COMMENTARY Response to the Comparison of Generic Ritonavir (Ritomune, Cipla) and Lopinavir/Ritonavir Tablets (Lopimune, Cipla) and the Abbott Brand (Norvir Soft-Gel Capsules and Kaletra Tablets) SIDDARTH CHACHAD, JAIDEEP GOGTAY, GEENA MALHOTRA, SHRINIVAS PURANDARE Department of Clinical and Bioequivalence Research, Cipla Ltd, Mumbai, India
Received 17 March 2009; revised 5 May 2009; accepted 16 May 2009 Published online 28 August 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21852
TO THE EDITOR: The availability of generic antiretroviral drugs has made a dramatic impact on morbidity and mortality of HIV/AIDS patients in the developing countries. These drugs which cost less than 10% of the innovator have led to a reduction in mortality rates of nearly 80% in India. With increasing use of first-line agents the challenge is now to provide cost effective second-line drugs, an important component of which are protease inhibitors. Recently, Dr. Kevin and colleagues from Abbott Laboratories, USA compared the bioavailability of generic Ritonavir (Ritomune, Cipla) and Lopinavir/Ritonavir Tablets (Lopimune, Cipla) with the innovator products in a dog model. Bioequivalence studies were conducted using a randomized, two-period crossover study design under fasting conditions in groups of 12 beagle dogs with a washout of 1 week between two periods. The concentrations of Lopinavir and Ritonavir were determined by HPLC-MS/MS and the point estimates for pharmacokinetic
Correspondence to: Siddarth Chachad (Telephone: þ91-222571-6016; Fax: þ91-22-2578-5298; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 572–573 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
572
parameters Cmax and AUC were calculated on a logarithmic scale for the comparison of the test versus the reference formulation. The study concluded that there was a significant variability in bioavailability amongst generic tablet products containing Lopinavir and Ritonavir. Published literature has shown marked intraindividual variability in case of the antiretroviral drugs including Ritonavir alone and in combination with Lopinavir.1 Considering the highly variable nature of the drug, we believe that a study conducted in 12 beagle dogs is not an adequately powered study to reach a conclusion. Further, a retrospective evaluation of using dog as animal model to study the fraction of oral dose absorbed in humans has shown overall poor correlation (r2 ¼ 0.5123).2 Also, as per the bioavailability data of Abbott, a significant percentage (25%, i.e., 4/16 studied formulations) showed no correlation between dog and man. Since all these are major limiting factors, no conclusion can be drawn based on the present dog study. The in vitro data of the test (Ritomune, Cipla) and reference (Norvir, Abbott) Ritonavir formulations has shown comparable dissolution profiles in release medium as per FDA-Recommended Dissolution Methods. More than 85% of the drug is dissolved within 15 min for both test and reference formulations. We have recently completed a
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
573
randomized, single dose, open label, two-period, two-treatment, crossover bioequivalence study of Lopimune (Lopinavir/Ritonavir Tablets 200 mg/ 50 mg manufactured by Cipla Ltd, India) with Kaletra1 (Lopinavir 200 mg and Ritonavir 50 mg) Tablets manufactured by Abbott Laboratories, USA in 72 healthy human subjects under fasting condition. The 90% confidence intervals for the ratio of the geometric means for log-transformed pharmacokinetic parameters Cmax, AUC0–72, and AUC0–inf calculated using SAS Version 9.1 software were clearly within the conventional bioequivalence range of 80–125%. Based on this large study, it was shown that the test and reference Lopinavir/Ritonavir Tablets 200 mg/50 mg were bioequivalent. A recent article presented at CROI conference in Boston early this year demonstrated the efficacy of generic protease inhibitors in patients with HIV/AIDS.3 Patients failing first-line non-nucleoside Reverse Transcriptase Inhibitor regimens (as per World Health Organization Anti-Retroviral Therapy guidelines) were switched to a combination of Protease Inhibitor/ritonavir PI/r (indinavir [IDV]/r, lopinavir [LPV]/r, saquinavir [SQV]/r, atazanavir [ATV]/r) þ 2 nucleoside Reverse Transcriptase Inhibitors. Median duration on first-line ART was 30 months. First-line ART failure was virologic failure (37%), immunologic failure (47%), and clinical failure (16%). Follow up was clinically initially monthly, then quarterly, CD4 counts 6 monthly and viral load at 6 months and annually. Effectiveness was defined as absence of virologic, immunologic, and clinical failure at each follow up visit. It was concluded
DOI 10.1002/jps
that the generic second-line PI/r-based regimens were effective irrespective of type of failure and duration of exposure to first-line ART. Giving due consideration that the results of the human bioequivalence trial on the Cipla’s generic product were not available to the authors of the original article at the time of submission, Cipla does acknowledge that the dog is a known model for studying pharmacokinetics and extrapolating bioequivalence in humans. However, understanding the public health perspective and the regulatory requirements for a generic product to show human bioequivalence, great caution should be exercised when interpreting the pharmacokinetic data extrapolated from study in animals.
REFERENCES 1. Nettles RE, Kieffer TL, Parsons T, Johnson J, Cofrancesco J, Jr., Gallant JE, Carson KA, Siliciano RF, Flexner C. 2006. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis 42:1189–1196. Epub 2006 Mar 7. Erratum in: Clin Infect Dis 2006 Sep 1; 43(5):672. 2. Chiou WL, Jeong HY, Chung SM, Wu TC. 2000. Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans. Pharm Res 17:135–140. 3. Pujari S, Dravid A, Gupte N, Dhananjay A, Menezes L, Sinnott J. 2008. Effectiveness and Safety of Generic Second-line PI-based ART in Western India. Boston: Presented at the 15th Annual Conference on Retroviruses and Opportunistic Infections.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
Received 17 March 2009; revised 5 May 2009; accepted 16 May 2009 Published online 28 August 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21852
TO THE EDITOR: The availability of generic antiretroviral drugs has made a dramatic impact on morbidity and mortality of HIV/AIDS patients in the developing countries. These drugs which cost less than 10% of the innovator have led to a reduction in mortality rates of nearly 80% in India. With increasing use of first-line agents the challenge is now to provide cost effective second-line drugs, an important component of which are protease inhibitors. Recently, Dr. Kevin and colleagues from Abbott Laboratories, USA compared the bioavailability of generic Ritonavir (Ritomune, Cipla) and Lopinavir/Ritonavir Tablets (Lopimune, Cipla) with the innovator products in a dog model. Bioequivalence studies were conducted using a randomized, two-period crossover study design under fasting conditions in groups of 12 beagle dogs with a washout of 1 week between two periods. The concentrations of Lopinavir and Ritonavir were determined by HPLC-MS/MS and the point estimates for pharmacokinetic
Correspondence to: Siddarth Chachad (Telephone: þ91-222571-6016; Fax: þ91-22-2578-5298; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 572–573 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
572
parameters Cmax and AUC were calculated on a logarithmic scale for the comparison of the test versus the reference formulation. The study concluded that there was a significant variability in bioavailability amongst generic tablet products containing Lopinavir and Ritonavir. Published literature has shown marked intraindividual variability in case of the antiretroviral drugs including Ritonavir alone and in combination with Lopinavir.1 Considering the highly variable nature of the drug, we believe that a study conducted in 12 beagle dogs is not an adequately powered study to reach a conclusion. Further, a retrospective evaluation of using dog as animal model to study the fraction of oral dose absorbed in humans has shown overall poor correlation (r2 ¼ 0.5123).2 Also, as per the bioavailability data of Abbott, a significant percentage (25%, i.e., 4/16 studied formulations) showed no correlation between dog and man. Since all these are major limiting factors, no conclusion can be drawn based on the present dog study. The in vitro data of the test (Ritomune, Cipla) and reference (Norvir, Abbott) Ritonavir formulations has shown comparable dissolution profiles in release medium as per FDA-Recommended Dissolution Methods. More than 85% of the drug is dissolved within 15 min for both test and reference formulations. We have recently completed a
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010
573
randomized, single dose, open label, two-period, two-treatment, crossover bioequivalence study of Lopimune (Lopinavir/Ritonavir Tablets 200 mg/ 50 mg manufactured by Cipla Ltd, India) with Kaletra1 (Lopinavir 200 mg and Ritonavir 50 mg) Tablets manufactured by Abbott Laboratories, USA in 72 healthy human subjects under fasting condition. The 90% confidence intervals for the ratio of the geometric means for log-transformed pharmacokinetic parameters Cmax, AUC0–72, and AUC0–inf calculated using SAS Version 9.1 software were clearly within the conventional bioequivalence range of 80–125%. Based on this large study, it was shown that the test and reference Lopinavir/Ritonavir Tablets 200 mg/50 mg were bioequivalent. A recent article presented at CROI conference in Boston early this year demonstrated the efficacy of generic protease inhibitors in patients with HIV/AIDS.3 Patients failing first-line non-nucleoside Reverse Transcriptase Inhibitor regimens (as per World Health Organization Anti-Retroviral Therapy guidelines) were switched to a combination of Protease Inhibitor/ritonavir PI/r (indinavir [IDV]/r, lopinavir [LPV]/r, saquinavir [SQV]/r, atazanavir [ATV]/r) þ 2 nucleoside Reverse Transcriptase Inhibitors. Median duration on first-line ART was 30 months. First-line ART failure was virologic failure (37%), immunologic failure (47%), and clinical failure (16%). Follow up was clinically initially monthly, then quarterly, CD4 counts 6 monthly and viral load at 6 months and annually. Effectiveness was defined as absence of virologic, immunologic, and clinical failure at each follow up visit. It was concluded
DOI 10.1002/jps
that the generic second-line PI/r-based regimens were effective irrespective of type of failure and duration of exposure to first-line ART. Giving due consideration that the results of the human bioequivalence trial on the Cipla’s generic product were not available to the authors of the original article at the time of submission, Cipla does acknowledge that the dog is a known model for studying pharmacokinetics and extrapolating bioequivalence in humans. However, understanding the public health perspective and the regulatory requirements for a generic product to show human bioequivalence, great caution should be exercised when interpreting the pharmacokinetic data extrapolated from study in animals.
REFERENCES 1. Nettles RE, Kieffer TL, Parsons T, Johnson J, Cofrancesco J, Jr., Gallant JE, Carson KA, Siliciano RF, Flexner C. 2006. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis 42:1189–1196. Epub 2006 Mar 7. Erratum in: Clin Infect Dis 2006 Sep 1; 43(5):672. 2. Chiou WL, Jeong HY, Chung SM, Wu TC. 2000. Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans. Pharm Res 17:135–140. 3. Pujari S, Dravid A, Gupte N, Dhananjay A, Menezes L, Sinnott J. 2008. Effectiveness and Safety of Generic Second-line PI-based ART in Western India. Boston: Presented at the 15th Annual Conference on Retroviruses and Opportunistic Infections.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 2, FEBUARY 2010