INTRODUCTION

Human immunodeficiency virus (HIV) infection is a major public health problem in the world and antiretroviral treatment prevents HIV-related illnesses. In Latin America, only 65% of cases receive treatment; in Peru ^1,2 the National Program for Highly Active Antiretroviral Therapy (HAART), through the Peruvian Ministry of Health (MINSA), works to control the HIV epidemic through prevention strategies, providing treatment free of charge, ensuring medication availability and adherence ³.

Ensuring that drugs meet quality standards is mandatory to guarantee the safety and efficacy of the drug. A generic or multisource drug (MD) is pharmaceutically equivalent (alternative) and may or may not be therapeutically equivalent to the innovator (reference). Only a MD that has demonstrated therapeutic equivalence to the innovator (in vivo or in vitro) is interchangeable ⁴. In the European Union and the United States of America, therapeutic equivalence is a regulatory requirement for generic drug registration ⁵.

Interchangeable generics are marketed in Mexico, Brazil and Argentina; however, in Bolivia, Honduras, Nicaragua, Dominican Republic and other countries such as Peru, pharmaceutical products are still marketed without therapeutic equivalence studies ⁶. In Peru, for the registration, inscription and re-inscription of drugs, the regulatory authority requests interchangeability studies through Supreme Decree 024-2018-SA, which is being applied in the country gradually or progressively, its first list included lamivudine (LMV) tablets, for which in vitro studies (bioexcencion) are accepted ⁷.

A drug must meet pharmacopeial requirements to demonstrate its quality, including the dissolution test that determines the percentage (%) of drug dissolved in a single point. To demonstrate in vitro therapeutic equivalence, in addition to the solubility and permeability of the drug, the similarity of the dissolution profiles (dissolved in several points) is evaluated, and the MD must show a behavior similar to that of the innovator. However, there are occasional reports of generic drugs of inferior quality worldwide ⁽⁸. In Peru, generic drugs that did not meet the required quality were found, among them, some batches of metformin hydrochloride 850 mg ⁹, moxifloxacin tablets 400 mg ¹⁰⁾ did not pass the dissolution profile similarity test. For this reason, it is imperative to investigate the quality of the drugs dispensed in the country, in this case LMV, a drug for the treatment of HIV provided by the HAART program of MINSA.

This study aimed to evaluate the quality and compare the similarity of the dissolution kinetics of two batches of MD LMV 150 mg tablets, from the HAART program of MINSA, through dissolution profiles compared to the innovative drug (reference) Epivir.

THE STUDY

The list of chemicals and reagents is available in the supplementary material.

FINDINGS

The validation results demonstrate that the method is linear over the concentration range of 0.0170 to 0.2037 mg/mL for all dissolution media. The values we obtained for the relative standard deviation (RSD) and recovery of standard solution samples indicate that the precision and accuracy of the method is satisfactory. The 0.45 μm PVDF filter type was selected because it had the highest % recovery among the evaluated filters, and the method was found to be stable at 24 h under refrigerated conditions (2 to 8 °C) (Table 2).

Dissolution profiles

We found that the dissolution profile results of LMV batches A and B were between 98.6% and 96.2% for pH 1.2; between 103.4% and 96.3% for pH 4.5 and between 106.1% and 89.5% for pH 6.8; at 15 min the percent dissolution in both cases was greater than 85%. Since both batches passed the in vitro test, it was not necessary to calculate the f2 (Figure 1). All samples, both multisource and innovative, met the WHO requirements for dissolution profiling. The difference between the percentage of active ingredient content of the reference product and the MDs was no more than 5%. Figure 1 shows the dissolution profiles of the LMV MDs marketed in Peru versus the data of the reference product.

Figure 1 Dissolution profiles of lamivudine tablets (150 mg) of multisource A and B versus innovator in the three dissolution media. 

DISCUSSION

Evaluating the biopharmaceutical quality of generic antivirals is a strategy to provide adherence to antiretroviral treatment in HIV patients and to reduce resistance to this drug with effective therapy ¹⁴. In this study all samples, both the innovator LMV drug and both batches of LMV MD, met pharmacopeial quality requirements for identification, content, dose uniformity and dilution. In addition, the two multisource drug batches A and B showed similarity between the percentages of drug recovered with the innovator drug at all three physiological pHs and the percentage of dissolution was greater than 85% at 15 min in both cases, so it was not necessary to calculate the f2.

In contrast to our results regarding quality, Fernandes et al. reported that two generic batches of LMV failed the quality test for dissolution ¹⁵. Later in 2015, Wang et al. reported that 6 of 88 samples (from developing countries and internet purchases) failed the dissolution test at 1.5-8.3%, below the standard range in a multicenter study ¹⁶.

Dissolution testing is a powerful quality tool associated with drug absorption and drug bioavailability. Problems associated with poor quality drugs lead to subtherapeutic treatments, adverse effects, morbidity, mortality, and drug resistance ⁴.

Regarding the dissolution profiles, our results agree with the study conducted in Turkey by Otzurk et al. which obtained more than 85% of the labeled amount dissolved in 15 min in the three-dissolution media: pH 1.2 (97.5%, 100.0% and 99.9%); pH 4.5 (96.4%, 101.0% and 99.8%); and pH 6.8 (103.0%, 98.8% and 100.0%); therefore, the mathematical comparison of similarity (f2) was not necessary either ¹⁷. On the contrary, a study carried out in Argentina showed that the results obtained for LMV and abacavir presented an f2 greater than 50 for the three generic lots for both LMV and abacavir at pH 1.2 and 6.8; however, for pH 4.5, lot 1 did not meet f2 for either of the two actives ¹⁸.

The similarity factor is a measure of the percent dissolution (%) between the two curves. Dissolution profiles are considered similar if the value of f2 is ≥50. However, when 85% or more of the stated amount of the test or reference drugs dissolve in ≤15 min using the recommended dissolution media (pH 1.2, pH 4.6, and pH 6.8), they are considered similar dissolution profiles without requiring any mathematical calculation ⁷.

A study in Brazil found that batches from laboratory G (reference) showed similarity among themselves with fast dissolution G1, G2 and G3 (97.9%; 101.8% and 99.4%); while laboratory A and B drugs showed differences among their batches A1, A2 and A3 (103.6%; 100.3% and 100.6%) and B1, B2 and B3 (98.8%; 100.7% and 101.2%), however, at the end of the determined time, they reached a performance similar to that of innovator G, being considered pharmaceutical equivalents to the reference drug. On the contrary, the batches of laboratory C were not similar to each other C1, C2 and C3 showing an alarmingly low dissolution 73.9%; 7.2% and 11.7% ¹¹.

A thorough evaluation of excipient similarity is critical and must be well established to demonstrate interchangeability (bioexcitation) ⁴. LMV exhibits characteristics of high solubility with the intrinsic dissolution method ¹⁹. One study presented the permeability of LMV as an active pharmaceutical ingredient (API) of high permeability (Class I) ²⁰, but it is classified as class III of low permeability because it has an elimination rate as unchanged drug via the kidney of approximately 70%, characteristic of this class of API.

The strength of this study lies in the fact that LMV is the first drug of the HAART program of MINSA to be evaluated in Peru. As for the limitations of this study, it was difficult to obtain the sample, and it was not feasible to obtain the qualitative-quantitative composition of the innovative drug and the MDs to evaluate the excipients. Solubility and permeability studies were not performed because they were not within the objectives of the study as requested by the WHO and the DS 024-2018 SA.

The procurement of drugs for MINSA’s health strategy programs guarantees access to these products for the population; however, they must be of proven quality, safety and efficacy, otherwise we will find ourselves immersed in a loss of confidence in the health systems and a waste of financial resources. It is important to consider these tests: quality and dissolution kinetics, as requirements in the purchasing process, even more so if it is an antiviral drug.

In conclusion, we found that LMV innovator, LMV MD A and LMV MD B met the pharmacopeial quality specifications and demonstrated similar dissolution profiles to the innovator in vitro, which shows that LMV 150 mg tablets have in vitro equivalence. It is recommended to continue implementing drug interchangeability studies so that the population has greater access to safe, quality and affordable MDs.