Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 6August 2016

This part outlines the scientific assessment and knowledge about this product at the time ofprequalification. Updates to this information are included in parts 1 to 5 and 8 of this WHOPAR.

SCIENTIFIC DISCUSSION

Name of the Finished Pharmaceutical
Product[HA573 trade name]*

Manufacturer of Prequalified Product

Macleods Pharmaceuticals Limited
Block No.: 2, Village Theda
P.O. Lodhi Majra
Tehsil Baddi
Distric.: Solan
Himachal Pradesh, 174101
India

Active Pharmaceutical Ingredient(s) (API)Lopinavir and ritonavir

Pharmaco-therapeutic group(ATC Code)

Antivirals for treatment of HIV infections, combinations(J05AR10)

Therapeutic indication[HA573 trade name] is indicated in combination with otherantiretroviral agents for the treatment of humanimmunodeficiency virus (HIV-1) infection in adults andchildren weighing
10 kg or more.

1.

Introduction[HA573 trade name] is indicated in combination with other antiretroviral agents for the treatment of
human immunodeficiency virus (HIV-1) infection in adults and children weighing 10 kg or more.
[HA573 trade name] should be initiated by a health care provider experienced in the management ofHIV infection.
2.

Assessment of quality

The assessment was done in accordance with the requirements of WHO’s Guidelines on submission ofdocumentation for a multisource (generic) finished pharmaceutical product for the WHO
Prequalification of Medicines Programme: quality part.
Active pharmaceutical Ingredient (API)Lopinavir
Lopinavir has four chiral centres and is known to exhibit polymorphism. The manufacture of lopinavir
entails several steps and is stereo-selectively producing the desired stereoisomer and the ‘type-I highlyhydrated crystal form’. The API produced is soluble in organic solvents like methanol, ethanol,
dichloromethane and DMF, but practically insoluble in water and in aqueous buffers across thephysiological pH range. It is slightly hygroscopic.

*Trade names are not prequalified by WHO. This is the national medicines regulatory authority’s responsibility.
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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 6

August 2016

The API specifications include tests for description, solubility, identification (IR, HPLC), watercontent, residue on ignition, heavy metals, organic impurities (HPLC), assay (HPLC), crystal form
(XRPD), specific optical rotation and residual solvents.
Stability testing was conducted according to the requirements of WHO. The proposed re-test period isjustified based on the stability results when the API is stored in the original packaging.
Ritonavir
Ritonavir is described in the Ph.Int, Ph.Eur. and USP. The API has four chiral centres, is practicallyinsoluble in water and is known to exhibit polymorphism, with various crystal forms. The
manufacture of ritonavir entails several steps and stereo-selectively produces the desired stereoisomer.
Polymorphic form I, characterised by the XRPD pattern, is consistently produced.
The API specifications are pharmacopoeial based and include tests for description, solubility,identification (IR, HPLC), heavy metals, water, residue on ignition, organic impurities (HPLC), assay(HPLC), crystal form (XRPD), specific optical rotation and residual solvents.
Stability testing was conducted according to the requirements of WHO. The proposed re-test period isjustified based on the stability results when the API is stored in the original packaging.
Other ingredients
Other ingredients used in the core tablet formulation include copovidone, sorbitan monolaurate,
colloidal silicon dioxide, anhydrous dibasic calcium phosphate and sodium stearyl fumarate. The
commercially sourced proprietary film-coating mixture contains polyvinyl alcohol-part hydrolysed,titanium dioxide, polyethylene glycol, talc and iron oxide yellow. TSE / BSE free certificates havebeen provided for the excipients.
Finished pharmaceutical product (FPP)
Pharmaceutical development and manufacture
The multisource product is a pale yellow coloured, capsule shaped, biconvex, film-coated tablets
debossed with “M31” on one side and plain on the other side. The tablets are packaged in an heavy
weight HDPE bottle with polypropylene child-resistant closure, also containing 2 sachets each filledwith 1 gm silica gel.
The development of the final composition of the tablets has been described. The objective was todevelop a stable product, bioequivalent to the comparator product, Kaletra® tablets of the samestrength. The tablets have been developed as solid dosage form for oral administration. As reported inliterature, lopinavir and ritonavir are practically insoluble in water, to such an extent that whenadministered as tablet prepared by conventional techniques, the oral bioavailability is negligible. Inorder to have clinically significant concentrations of these APIs, tablets containing the lopinavir andlopinavir in solid dispersion form were developed. Different techniques to prepare the solid dispersion(solubilisation of the APIs and adsorbing them on solid material, co-precipitation and solvent
evaporation) were explored during development. Based on development studies, the solvent
evaporation technique was selected. Appropriate in-process controls were set to ensure batch-to-batch
reproducibility.
Two tablet strengths (200mg/50mg and 100mg/25mg), proportionally similar in composition andmanufactured according to the same procedure, were developed. Comparative in-vitro dissolution
studies showed that Lopinavir/Ritonavir 100mg/25mg Tablets have similar in vitro dissolution
characteristics to the higher strength, which was used bioequivalent studies, in the media studied. It
has furthermore been demonstrated that the multipoint dissolution characteristics of the multisource
product and the amorphous nature of the APIs are retained during shelf life.

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 6

August 2016

Specifications
The finished product specifications include tests for description, identification of the APIs (HPLC,TLC), average weight, dissolution (2 point; HPLC detection), uniformity of dosage units (by contentuniformity), organic impurities (HPLC), assay (HPLC), water content, residual solvents, microbialenumeration and specified microorganisms and XRPD (for detection of API crystalline forms).
Stability testingStability studies have been performed at 30C/75%RH as long-term storage conditions and for six
months at accelerated conditions in the packaging intended for marketing of the product. The data
showed little change with time and were well within the agreed specifications at both storage
conditions. No change in the solid state form of the APIs could be detected. Based on the available
stability data, the proposed shelf life and storage conditions as stated in the SmPC are acceptable.
Conclusion
The quality part of the dossier is accepted.
3.

Assessment of bioequivalence

The following bioequivalence study has been performed in 2012 according to internationally accepted
guidelines.
Bioequivalence study of two tablets as single dose of fixed dose combination of Lopinavir andRitonavir tablets 200 mg / 50 mg (each tablet contains lopinavir USP 200 mg and ritonavir USP 50mg) manufactured by Macleods Pharmaceuticals Ltd., India in comparison with two tablets ofKaletra® (lopinavir/ ritonavir) tablets 200 mg / 50 mg (each tablet contains 200 mg lopinavir and 50mg ritonavir) manufactured for Abbott Laboratories, USA in healthy, adult, human subjects underfasting condition (study no. BEQ-806-LR(F)-2011).
The objective of the study was to compare the bioavailability of the stated Lopinavir/Ritonavir
200mg/50mg FDC tablet manufactured by Macleods Pharmaceuticals Ltd., India (test drug) with thereference formulation Kaletra® (Abbott Laboratories) and to assess bioequivalence. The comparison
was performed as a single centre, open label, randomized, crossover study in healthy subjects underfasting conditions. Each subject was assigned to receive each of the following two treatments in arandomized fashion:
Treatment T:

Test – 2 tablets Lopinavir/Ritonavir 200mg/50 mg(lopinavir 400 mg + ritonavir 100mg)
Batch no. BLW202A.

Treatment R:Reference – 2 tablets Kaletra®
(lopinavir 400 mg + ritonavir 100mg)
Batch no. 08411AA

A 7-day wash-out period was observed between administration of test and reference. Serial blood
samples (1 pre-dose sample and 24 samples within 48h post dose) were taken during each study
period to obtain bioavailability characteristics AUC, Cmax and tmax for bioequivalence evaluation. Drugconcentrations for lopinavir and ritonavir were analyzed using a validated LC-MS/MS method. The
limit of quantification was stated to be about 202 ng/ml for lopinavir and about 15 ng/ml for ritonavir.
The study was performed with 72 participants; data generated from a total of 63 subjects were utilized
for analysis to establish pharmacokinetic parameters and assess bioequivalence.

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 6

August 2016

Arithmetic mean and geometric mean values of the pharmacokinetic variables for lamivudine andtenofovir as well as statistical results are summarised in the following tables:
LopinavirPharmacokineticParameter

Test formulation (T)arithmetic mean ± SD
(geometric mean)

Reference (R)arithmetic mean ± SD
(geometric mean)

log-transformed parameters

Ratio
T/R (%)
tmax (h)Cmax (ng/mL)
AUC0-t (ng.h/mL)
AUC0-inf (ng.h/mL)

3.70 ± 0.927669 ± 2095
(7386)
102339 ± 37491(95807)110837 ± 40784(103554)

3.81 ± 1.05
7727 ± 1784
(7537)
101239 ± 34535(96090)109720 ± 36669(104104)

Test formulation (T)arithmetic mean ± SD
(geometric mean)

Reference (R)arithmetic mean ± SD(geometric mean)

98.0

Conventional
90% CI(ANOVAlog)
93.1 – 103.2

99.7

93.6 – 106.2

99.5

93.5 – 105.8

Ritonavir
PharmacokineticParameter

log-transformed parameters

Ratio
T/R (%)
tmax (h)Cmax (ng/mL)
AUC0-t (ng.h/mL)
AUC0-inf (ng.h/mL)

3.75 ± 0.90
633 ± 323
(554)
5197 ± 2413
(4644)
5474 ± 2496
(4909)

3.60 ± 1.04
609 ± 285
(551)
5090 ± 2217
(4651)
5347 ± 2252
(4908)

100.5

Conventional
90% CI(ANOVAlog)
91.8 – 110.0

99.8

92.9 – 107.3

100.0

93.4 – 107.2

Conclusions:
The results of the study show that preset acceptance limits of 80 -125 % are met by both AUC andCmax values regarding lopinavir and ritonavir. Accordingly, the test FDC tablet Lopinavir/Ritonavir
200mg/50mg meets the criteria for bioequivalence with regard to the rate and extent of absorption andis therefore bioequivalent to the reference Kaletra® (Abbott Laboratories).
A biowaiver was granted for [HA573 trade name] (Macleods Pharmaceuticals Ltd., India) inaccordance to WHO guideline. In comparison with the strength of the test FDC product used in thebioequivalence study, the [HA573 trade name] was determined to be qualitative essential the same,the ratio of active ingredient and excipients between the strengths is considered essential the same andthe dissolution profiles between the formulations for the API was determined the same.

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

4.

WHOPAR Part 6

August 2016

Summary of product safety and efficacy[HA573 trade name] has been shown to conform to the same relevant standards of quality, efficacy
and safety as those required of the comparator product. According to the submitted data on quality
and bioavailability, [HA573 trade name] is pharmaceutically and therapeutically equivalent and thusinterchangeable with the comparator product Kaletra® (Abbot Laboratories, USA) for which benefits
have been proven in terms of clinical efficacy. The clinical safety of [HA573 trade name] isconsidered acceptable when guidance and restrictions stated in the summary of product characteristics(SmPC) are considered. Refer to the SmPC (WHOPAR part 4) for data on clinical safety.
5.

Benefit risk assessment and overall conclusion

Quality
Physicochemical and biological aspects relevant to the uniform pharmaceutical characteristics havebeen investigated and are controlled in a satisfactory way. The quality of this product is considered tolead to an acceptable clinical performance when [HA573 trade name] is used in accordance with theSmPC.
Bioequivalence[HA573 trade name] fulfilled all criteria for waiving an in-vivo bioequivalence study as per relevant
WHO guidance. Hence [HA573 trade name] and Kaletra® (Abbot Laboratories, USA) can beconsidered bioequivalent.
Efficacy and SafetyRegarding clinical efficacy and safety, [HA573 trade name] is considered effective and safe to use
when the guidance and restrictions in the SmPC are taken into consideration.
Benefit Risk Assessment
Based on WHO's assessment of data on quality, bioequivalence, safety and efficacy the team ofassessors considered that the benefit–risk profile of [HA573 trade name] was acceptable for thefollowing indication: 'for the treatment of HIV-1 in combination with other antiretroviral agents inadults and children weighing 10 kg or more', and would allow inclusion of [HA573 trade name],manufactured at Macleods Pharmaceuticals Limited, Block No.: 2, Village Theda, P.O. Lodhi Majra,
Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India in the list of prequalified medicinal
products.

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