Marcelo Gomes Davanço

Background: Multiple myeloma (MM) is a mature B-cell disorder characterized by the excessive production of monoclonal immunoglobulins. It is the second most common hematological cancer and predominantly affects older adults. In 2022, there were approximately 188,000 MM new cases worldwide. The disease is associated with a relapsing–refractory course. First-line therapies are often insufficient, making additional treatment options necessary. For patients refractory to lenalidomide and proteasome inhibitors (bortezomib and/or carfilzomib), pomalidomide combined with dexamethasone and an additional active agent can be used as a therapeutic strategy. Objective: This study was conducted to evaluate the bioequivalence and tolerability of two pomalidomide hard capsule formulations to support regulatory approval of a branded generic product in Latin American countries. Methods: An open-label, randomized, single-dose, two-treatment, two-sequence, two-period crossover study was conducted in healthy male subjects. Participants received a single oral dose of the test product, Xetrane^® 4 mg hard capsule (Laboratório LKM S.A., Argentina), and the reference product, Imnovid^® 4 mg hard capsule (Celgene International Sàrl), with a 7-day washout period. Blood samples were collected over 48 h post-dose. Plasma pomalidomide concentrations were determined using a validated LC-MS/MS method, and pharmacokinetic parameters were estimated using non-compartmental analysis. Findings: Thirty-four subjects were enrolled, and 29 completed the study. Geometric mean ratios (90% confidence intervals) for Cmax and AUC_0–t were 106.24% (100.77–112.00) and 94.67% (91.61–97.82), respectively. Both formulations were well tolerated. Bioequivalence between Xetrane^® and Imnovid^® was demonstrated in accordance with regulatory criteria. NCT07694011.

Background: Globally, breast cancer is the most frequently diagnosed neoplasm among women, with an estimated 2.3 million new cases reported in 2022. Treatment for hormone receptor-positive (HR+) advanced breast cancer includes aromatase inhibitors and CDK4/6 inhibitors such as palbociclib. Objective: This study evaluated the bioequivalence and tolerability of two palbociclib capsule formulations to support the regulatory approval of a branded generic product in Latin America countries. Methods: Healthy participants were enrolled in an open-label, randomized, single-dose study using a two-treatment, two-sequence, two-period crossover design. Study participants received a single-dose test product, a palbociclib 125 mg capsule (Laboratório LKM S.A., Argentina), and a reference product, an Ibrance^® 125 mg capsule (Pfizer Manufacturing Deutschland GmbH), under fed conditions separated by a 14-day washout period. Blood samples were obtained at scheduled intervals over a 72 h period following administration, and the palbociclib plasma concentrations were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were computed via non-compartmental analysis methods. A total of 52 healthy subjects were enrolled, and 50 subjects completed the study. Results: The geometric mean ratios (90% confidence intervals) for C_max and AUC_0–72 were 107.07% (101.98–112.42) and 109.77% (106.51–113.13), respectively. Conclusions: Both formulations were well-tolerated in healthy subjects. In accordance with regulatory standards, bioequivalence between the test formulation and the reference product was successfully demonstrated.

Background and Objective: Buprenorphine is an opioid drug indicated for the management of severe and persistent pain. The buprenorphine transdermal patch provides a non-invasive method of rate-controlled drug release, ensuring constant and predictable drug plasma levels over an extended period. This study aimed to assess the bioequivalence, skin adhesion non-inferiority, and tolerability of two buprenorphine transdermal patches to meet the regulatory requirements for the registration of a generic product in Brazil. Methods: A randomized, single-dose, two-period, two-sequence crossover trial was performed involving healthy subjects of both genders. The subjects received a single dose of either the test formulation or the reference formulation (Restiva^®), separated by a 29-day washout period. For pharmacokinetic analysis, blood samples were collected up to 12 days post-dose and quantified using a validated bioanalytical method. Skin adhesion was assessed over a 7-day period (dosing interval) following patch application. Seventy-six subjects were enrolled and fifty-two completed the study. Results and Conclusion: The 90% confidence intervals for Cmax, AUC_0–t, and partial AUCs were within the acceptable bioequivalence limits of 80 to 125%. Adhesion comparison showed the non-inferiority of the test formulation. Based on ANVISA’s regulatory requirements, the test and reference formulations were considered bioequivalent and could be interchangeable in clinical practice.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed‐dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open‐label, randomized, single‐dose, 2‐period, 2‐way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed‐dose combination tablets with a 7‐day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography‐tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration‐time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%‐125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

Etoricoxib is a non-steroidal anti-inflammatory drug with high selectivity for cyclooxygenase 2 (COX-2), exerting a pronounced anti-inflammatory effect with fewer adverse events when compared to COX-1 inhibitors. The present study aimed to evaluate the bioequivalence between two etoricoxib-coated tablet formulations to meet regulatory requirements for a branded generic product registration in Brazil. A crossover study with an open-label, randomized design and a single-dose regimen with two treatments and two periods was conducted on healthy Brazilians of both genders. Subjects randomly received a single dose of a 90 mg etoricoxib coated tablet of test product Xumer^® 90 mg (Adium S.A.) and the reference product Arcoxia^® 90 mg (Merck Sharp & Dohme Farmacêutica Ltda.) under fasting conditions separated by a 14-day period. Blood samples were collected sequentially for up to 96 h following drug administration, and the concentrations of etoricoxib in plasma were determined using a validated UPLC-MS/MS method. Pharmacokinetic parameters were computed utilizing non-compartmental analysis methods. A total of 32 healthy subjects were enrolled, and 25 subjects completed the study. Geometric mean ratios (90% confidence intervals) for C_max, AUC_0-t, and AUC_0-inf were 103.98% (95.63–113.06), 96.82% (91.82–102.09), and 95.79% (90.70–101.16), respectively. In accordance with regulatory standards, the test formulation (Xumer^® 90 mg) has been deemed bioequivalent to the reference product (Arcoxia^® 90 mg). As a result, these formulations can be considered interchangeable in clinical practice, with both proving to be safe and well-tolerated. The need for in vivo testing for the Xumer^® 60 mg strength was waived due to the proportional similarity of the formulations and the similar in vitro dissolution profiles observed across the various strengths.

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children’s school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets to meet regulatory requirements for registration in Brazil. Two independent studies (under fasting and fed conditions) designed as open-label, randomized, single-dose, two-period, two-way crossover trials were conducted in healthy subjects of both genders. Subjects were enrolled and randomly received a single dose of the test formulation methylphenidate hydrochloride 54 mg extended-release tablet (Consiv^®, Adium S.A., São Paulo, Brazil) or the reference formulation (Concerta^®, Janssen-Cilag Farmacêutica Ltd., São Paulo, Brazil), in each period, with a 7-day washout interval. Serial blood samples were collected up to 24 h post dose and methylphenidate plasma concentrations were obtained using a validated LC-MS/MS method. A total of 96 healthy subjects were enrolled in the fasting study, of which 80 completed the study. For the fed study, 52 healthy subjects were enrolled, and 46 subjects completed it. In both studies, 90% confidence intervals for Cmax, AUC_0–t, AUC_0–inf, and partial AUCs were within the acceptable limits of 80.00 to 125.00%. Thus, according to regulatory requirements, the test formulation (Consiv^®) was considered to be bioequivalent to the reference formulation (Concerta^®) in both conditions (fasting and fed) and, therefore, it can be considered interchangeable in clinical practice. Both formulations were safe and well tolerated in single-dose administration.

Rivaroxaban is an anticoagulant (orally active direct Xa inhibitor) considered to reduce the risk of stroke and systemic embolism and treat deep vein thrombosis, pulmonary embolism, and other cardiovascular complications. Bioanalytical methods for rivaroxaban quantification in plasma are necessary for application in pharmacokinetic studies, as well as in drug therapeutic monitoring. In this work, we developed and validated a sensitive bioanalytical method using LC–MS/MS for rivaroxaban quantification in human plasma using an one‐step liquid–liquid extraction. The linear concentration range was 1–600 ng/mL. The bioanalytical method was also applied to pharmacokinetic studies in healthy volunteers under fasting and fed conditions. The results demonstrated that the method is rapid, sensitive, and adequate for application in pharmacokinetic studies.

Lipases are one of the most used enzymes in the pharmaceutical industry due to their efficiency in organic syntheses, mainly in the production of enantiopure drugs. From an industrial viewpoint, the selection of an efficient expression system and host for recombinant lipase production is highly important. The most used hosts are Escherichia coli and Komagataella phaffii (previously known as Pichia pastoris) and less often reported Bacillus and Aspergillus strains. The use of efficient expression systems to overproduce homologous or heterologous lipases often require the use of strong promoters and the co-expression of chaperones. Protein engineering techniques, including rational design and directed evolution, are the most reported strategies for improving lipase characteristics. Additionally, lipases can be immobilized in different supports that enable improved properties and enzyme reuse. Here, we review approaches for strain and protein engineering, immobilization and the application of lipases in the pharmaceutical industry.

The objective of this study was to develop a dissolution test in order to establish an in vitro–in vivo correlation (IVIVC) model for desvenlafaxine succinate monohydrate (DVSM) extended release (ER) tablets. The in vitro release characteristics of the drug were determined using USP apparatus 1 at 75 rpm, with volume of HCl pH 1.2, acetate buffer solution (ABS) pH 4.5, or phosphate buffer solution (PBS) pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in healthy volunteers were obtained from a bioequivalence study. The similarity factors f₁ and f₂ were used to compare the dissolution data. The IVIVC model was developed using fraction dissolved and fraction absorbed of the reference product. For predictability, the results showed that the percentage prediction error (%PE) value of C_max was 7.63%. The observed low prediction error for C_max demonstrated that the IVIVC model was valid for this parameter.