Atazanavir is an antiretroviral drug of the protease inhibitor (PI) class. Like other antiretrovirals, it is used to treat
infection of human immunodeficiency virus (HIV) and used in combination with other HIV medications.
OFFICE OF GENERIC DRUG (US FDA)
RECOMMENDATION FOR
BIOEQUIVALENCE STUDY:
To ensure the safety and efficacy US FDA has laid some guidelines and recommendation to generic companies to follow. Similarly, Office of Generic Drug (OGD), US FDA, has recommended the bioequivalence study for the Atazanavir sulfate Capsules. OGD has recommended two (Fasting and Fed) studies with normal healthy male and females, general population. Single-dose, two-way crossover in-vivo study with 300 mg strength has been recommended for the BE studies. Atazanavir has to be measured in the plasma.
DOSAGE AND ADMINISTRATION
The US FDA approved patient information leaflet of Reyataz states general dosing recommendations as follow-
REYATAZ Capsules must be taken with food.
Therapy –naive patient:Reyataz 400 mg (Two 200 mg capsules) once daily taken with food
Therapy –Experienced patient:Reyataz 300 mg (one 300 mg capsule or two 150mg capsules) once daily plus Ritonavir 100 mg once a daily taken with food.
REYATAZ without Ritonavir is not recommended for treatment-experienced patients with prior virologic failure.
Food Effect: Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ (Atazanavir sulfate) with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state.
A CONTRARY VIEW
The BE recommendation for Atazanavir Sulfate Capsules is two way, cross over, in vivo study with 300 mg strength in both fasting and fed condition. A contrary view for this recommendation has been discussed in this section.
Clinical study conducted for Atazanavir shows that most of the study has been conducted either with 400 mg dose and/or 300 mg Atazanavir +100 mg Ritonavir. The pharmacokinetic stated in the approved patient information leaflet is based on the study conducted with Atazanavir 400 mg (two 200mg capsules) and Atazanavir 300mg + Ritonavir 100 mg in fed conditions. The summary basis of approval states that as there was very little change in the clinical study formulation and to be marketed formulation, no bioequivalence study was carried out.
To reduce the pill burden FDA has approved the 300 mg formulation to replace the two 150 mg capsules on October 20, 2006. Bioequivalence Study of Atazanavir 300 mg Capsule has been conducted against two 150 mg Atazanavir capsules sponsored by Bristol-Myers Squibb (ClinicalTrials.gov Identifier: NCT00393328). The purpose of this clinical research study is to assess the bioequivalence of atazanavir administered as a single 300 mg capsule relative to two atazanavir 150 mg capsules in healthy subjects. Interestingly this study was also conducted with 100 mg Ritonavir. Table2, above, mentions details of bioequivalence study of atazanavir 300 mg Capsule sponsored by Bristol-Myers Squibb
The dosage and administration states that Reyataz must be taken with food. Further the recommended dosages are 400 mg Atazanavir daily once or 300 mg Atazanavir with 100 mg Retonavir. The suggested dosage and administration could be based on the metabolism of the Atazanavir in the liver. Atazanavir is assumed to be highly variable drug. The variability is reduced when administered with food. Also Atazanavir shows nonlinear pharmacokinetics. The pharmacokinetic parameters (Cmax and AUC) for Atazanavir 300 mg + 100 mg Ritonavir are much higher for Atazanavir 400 mg.
Compared with Atazanavir 400 mg QD data, administration of Atazanavir /Ritonavir 300/100 mg QD increased the Atazanavir geometric mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively.
Based on the information the recommendation could be considered for the revision. The possible recommendation could be either one of the following:
Only Fed study with 300 mg Atazanavir.
Justification: Dosage recommendation states Atazanavir must be taken with food. Also food enhances bioavailability and reduces pharmacokinetic variability.
Bioequivalence study with 400 mg Atazanavir (Two 200 mg capsules) with food.
Justification: Dosage recommendation states Atazanavir 400 mg once daily. Pharmacokinetic is non-linear.
Bioequivalence study with 300 mg Atazanavir + 100 mg Ritonavir (Norvir)
Justification: Dosage recommendation states Atazanavir 300 mg once daily plus Ritonavir 100 mg once daily with food. Both Ritonavir and Atazanavir is metabolized in liver and the pharmacokinetic parameters are significantly higher than 400 mg Atazanavir alone.
References:
FDA-Approved Patient Labeling for REYATAZ (Atazanavir Sulfate Capsules), Bristol-Myers Squibb Company Princeton, NJ 08543 USA.
Details of bioequivalence study of Atazanavir 300 mg Capsule sponsored by Bristol-Myers Squibb. www.ClinicalTrials.gov
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