[e-med] Quelques études sur la qualité des ARV

[remed@remed.org]

E-MED: Quelques études sur la qualité des ARV
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[Pour ceux qui sont intéressés quelques réultats d'études publiées lors de
la 11ème conférence sur les rétrovirus et les infections opportunistes.CB]

Date: Tue, 02 Mar 2004 14:34:41 -0500
To: healthgap@critpath.org,
	"ip-health@lists.essential.org" <ip-health@lists.essential.org>
From: "George M. Carter" <fiar@verizon.net>
Cc: "ATAC" <atac-discuss@yahoogroups.com>
Subject: [Ip-health] Generics Just as Good

A number of studies at the recent 11th Conference on Retroviruses and
Opportunistic Infection underscored the bioequivalence of various generic
antiviral medications. See below.

Don't forget that you can also review a number of the sessions from the
CROI (but only practically if you have access to a high-speed internet
connection).
George M. Carter

***

http://www.retroconference.org/2004/cd/Abstract/581.htm
581
Antiretroviral Drug Content in Products from Developing Countries
S Penzak*1, E Acosta2, M Turner2, J Tavel3, and H Masur1
1Clin. Ctr., NIH, DHHS, Bethesda, MD, USA; 2Univ. of Alabama at Birmingham,
USA; and 3NIAID, NIH, DHHS, Bethesda, MD, USA

Background: Generic and discounted brand name antiretroviral (ARV)
medications are becoming increasingly available in developing countries. To
date, little information is available on drug content versus label claims
for these medications. The purpose of this study was to assess drug content
compared to the labeled amount among ARV obtained from developing countries.

Methods: We analyzed 6 ARV medications from 6 manufacturers and 4
international sources (Lithuania, South Africa, Jamaica, and Zambia). In
total, 12 different lots of medication were obtained in hospital or
commercial clinic pharmacies and brought to the United States
unrefrigerated. Drugs were then assessed for active ingredient. Drug
manufacturers included BMS (efavirenz, 1 lot), Merck (efavirenz, 1 lot;
indinavir, 3 lots), Aurobindo Pharma Ltd. (indinavir, 1 lot), Abbott
(lopinavir/ritonavir, 1 lot; ritonavir, 2 lots), GSK (amprenavir, 1 lot),
and Roche (saquinavir soft gel caps, 2 lots). Drug content was determined
with HPLC; a modified United States Pharmacopeia (USP) Uniformity of Dosage
Units test was applied; this test specifies that the drug content of an
individual capsule be within 85 to 115% of the label claim. For all
analyses, 2 to 4 capsules were assayed 6 to 9 times per dosage unit. Drug
content (percent of label claim) and coefficient of variation are reported.

Results: With the exception of ritonavir, which was not stored under
continual refrigeration, the active ingredient in each of the drug products
was within USP specifications; drug content was between 88 and 115% of
labeled amounts. The absolute value of the mean difference between measured
and labeled drug content was 7.7% and the median difference was -2.0%.
Amprenavir, from a single international source, was tested after its
expiration date and contained 92% of its labeled amount. Ritonavir content,
by itself and combined with lopinavir, was between 81 and 84% of the
labeled amount in tested preparations. The coefficient of variation among
capsules in individual lots was less than 10.2% for ritonavir and less than
8.9% for all other tested medications.

Conclusions: These quality-control data among generic and branded ARV are
encouraging; they also highlight the importance of storing
ritonavir-containing products under continual refrigeration in accordance
with manufacturer specifications. Continued quality-control, as well as
bioequivalence studies are necessary to identify inferior and/or
counterfeit ARV in developing countries.


***
http://www.retroconference.org/2004/cd/Abstract/582.htm
582
Quality Assurance of Generic Antiretroviral Formulations in India
G Ramachandran*1, E S Perloff2, L L von Moltke2, S Swaminathan1, and D J
Greenblatt2
1Tuberculosis Res. Ctr., Indian Council of Med. Res., Chennai, India and
2Tufts Univ. Sch. of Med., Boston, MA, USA

Background: India is a major producer of generic HIV antiretroviral drugs.
These are widely used in developing countries since they are cheaper than
those produced elsewhere. However, data describing the integrity of these
drugs are not publicly available. We analyzed the content of 6 commonly
used nucleoside and non-nucleoside reverse transcriptase inhibitors alone
and in combination from 3 Indian sources and compared the values with
proprietary medications that are manufactured in United States.

Methods: Efavirenz (600 mg), nevirapine (200 mg), zidovudine (300 mg),
stavudine (30 mg), lamivudine (150 mg), and a combination pill containing
nevirapine, stavudine, and lamivudine in the same dosages--obtained from
Aurobindo Pharma, Ranbaxy, and Cipla--were tested in this study. Zidovudine
and lamivudine in syrup preparations were also tested. The concentration of
all the antiretroviral formulations was determined by HPLC. Six tablets or
capsules of each anti retroviral drug were processed and analysed in
duplicate. The drugs were dissolved in methanol for analysis and
appropriate dilutions were made in methanol. After coding them, 12
chromatographic analyses were performed for each individual tablet. The
concentration of the drugs were calculated from a set of calibration
standards of known concentration.

Results: The mean drug content of all the preparations compared well with
the proprietary formulations and the variability ranged from 0.01 to 8.3%.
All the formulations were within 5% range of the stated contents as
compared to the proprietary drugs except for stavudine (single pill) and
lamivudine (combination pill) which were slightly higher.

Conclusions: Analyses of the above commonly used antiretroviral medications
manufactured in India by Aurobindo Pharma, Ranbaxy, and Cipla indicate that
the amount of active drug is very similar to those medications manufactured
in United States. Although these data are reassuring given the widespread
use of such products in the developing world, further studies are required
to evaluate the bioequivalence, including bioavailability, of these
medications over a larger sample size.

****

http://www.retroconference.org/2004/cd/Abstract/615.htm
615
A Comparison of the Pharmacokinetics of Ritonavir Boosted Generic
(Inhibisam) versus Brand Indinavir
C Zala*1, C S Alexander2, C Ochoa 1, S Guillemi2, L S Ting2, J J Asselin2,
P Cahn1, and J S G Montaner2
1Fndn. Huesped, Buenos Aires, Argentina and 2British Columbia Ctr. for
Excellence in HIV/AIDS, Vancouver, Canada

Background: Generic antiretrovirals are increasingly used in
resource-limited settings, often in the absence of independent
pharmacokinetic, safety or efficacy testing. In this cross-over study,
detailed 12-hour steady-state exposures to indinavir (IDV) obtained from a
generic formulation (Inhibisam) widely used in Argentina were compared to
brand IDV (Crixivan) to determine whether the 2 formulations afforded
similar exposures.

Methods: Steady-state pharmacokinetic profiles were obtained for 10
patients receiving a 2-daily regimen consisting of 2 NRTI plus
IDV/ritonavir (RTV) (800/100 mg). Five patients were initially prescribed
generic IDV while 5 were receiving Crixivan. Blood samples were taken
immediately prior to the morning dose of IDV/RTV and then at 0.5, 1, 2, 4,
6, 8, 10, 12 hours post-dose. Patients were then switched to receive the
alternative formulation of IDV and the pharmacokinetic were reassessed in
the same way. Plasma IDV concentrations were determined by a validated
assay utilizing high performance liquid chromatography coupled with tandem
mass spectrometry. Pharmacokinetic parameters (Ctrough [12 hour post dose],
Cmax, AUC0-12) were compared by parametric and non-parametric methods.

Results: On 10 patients, 20 evaluations were conducted. All had
completed >24 weeks of successful combination therapy (plasma viral load
<50 copies/mL). The IDV Ctrough, Cmax and AUC0-12 were not significantly
different for the two sources of IDV (see table below). Plasma HIV RNA
remained <50 copies/mL at the time of the second pharmacokinetic assessment
for all patients.
(see website for table)

See also:
http://www.retroconference.org/2004/cd/Abstract/583.htm
http://www.retroconference.org/2004/cd/Abstract/584.htm
http://www.retroconference.org/2004/cd/Abstract/591.htm

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