Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

A crossover study to evaluate the pharmacokinetics and bioequivalence of hydroxychloroquine tablets in healthy Chinese subjects.

AIMS: Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. MATERIALS AND METHODS: This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. RESULTS: A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in Cmax, AUC0-72h, and T1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on Cmax and T1/2 (p < 0.05), but AUC0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of Cmax and AUC0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. CONCLUSION: The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Bioequivalence study of two formulations of afatinib dimaleate tablets in healthy subjects under fasting conditions: A randomized, open-label, single-dose, crossover trial.

OBJECTIVE: To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles. MATERIALS AND METHODS: This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120 hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit. RESULTS: Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC0-t, 90.26 - 105.52% for Cmax, and 93.49 - 104.05% for AUC0-∞. CONCLUSION: The 90% CI for the geometric mean ratios (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.

Evaluation of the antiplatelet effect of generic ticagrelor 90 mg (ticaspan ® ) alone and in combination with aspirin 75 mg as compared to ticagrelor (innovator): An in vitro study.

OBJECTIVE: To evaluate an in vitro antiplatelet effect of generic ticagrelor 90 mg (ticaspan) alone and in combination with aspirin 75 mg as compared to the innovator formulation of ticagrelor alone and in combination with aspirin among healthy Indian volunteers. METHODS: 18 volunteers were enrolled and platelet viability was tested using lactate dehydrogenase (LDH) assay in six of 18 volunteers. In 12 volunteers, maximum platelet aggregation (MPA) and percentage inhibition of platelet aggregation (PI) were assessed using a platelet aggregometer in six study groups. RESULTS: There was no significant increase in LDH levels when platelets were incubated with an innovator or generic drug alone and in combination with aspirin as compared to the dimethyl sulfoxide [DMSO] group. All five study groups showed a significant reduction in the MPA values compared to the DMSO group ( P < 0.01). The extent of decrease in MPA observed with the generic drug was not significantly different from the innovator drug ( P = 0.325). Similarly, the MPA observed with the two combination groups did not differ from each other ( P = 1.000), but it was significantly different from the MPA observed with aspirin ( P = 0.039, each). The PI of platelet aggregation was significantly more in four study groups [generic drug alone; innovator alone; generic drug + aspirin; and innovator drug + aspirin] ( P < 0.01) as compared to the aspirin group. CONCLUSION: The generic ticagrelor and its combination with aspirin demonstrated an antiplatelet effect equivalent to the innovator drug and its combination with aspirin.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil. A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®). The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits. The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

Evaluation of the Physicochemical Properties of the Iron Nanoparticle Drug Products: Brand and Generic Sodium Ferric Gluconate.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme.

The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jurisdictions was a case-by-case approach given that most jurisdictions do not have well defined guidelines to support all possible scenarios. Even in the simplest case of intravenous solutions, the acceptability of qualitative changes in excipients differ between the IPRP members.  Notwithstanding the differences, the dissemination of the information is a first step towards regulatory convergence regarding biowaivers for certain dosage forms and should be useful for pharmaceutical companies currently developing generic medicinal products for IPRP jurisdictions.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

Bioequivalence of a Generic Nateglinide Formulation in Healthy Chinese Volunteers under Fasting and Fed Conditions: A Randomized, Open-Label, Double-Cycle, Double-Crossover Study.

INTRODUCTION: Nateglinide or N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine is a drug with a rapid hypoglycemic effect that is mainly used in the treatment of type 2 diabetes. Very few studies have assessed bioequivalence based on feeding status. This study aimed to assess the pharmacokinetic bioequivalence and safety of nateglinide-containing tablets (0.12 g) in healthy Chinese volunteers under fasting and fed conditions. METHODS: The studies were performed in 2017-2018 in the Phase I Clinical Trial Ward of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China. Eligible Chinese volunteers received a single 0.12-g dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. Blood samples were collected at various time intervals, and plasma nateglinide concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Then, the adverse events, laboratory test results, vital signs, and physical exam findings were compared between the 2 groups. RESULTS: The ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf of the tested to reference preparations under fasting conditions were 105.03% (90% confidence interval [CI]: 99.53-110.83%), 104.02% (90% CI: 101.37-106.74%), and 104.04% (90% CI: 101.38-106.77%), respectively. The same ratios under fed conditions were 96.55% (90% CI: 85.80-108.65%), 103.08% (90% CI: 100.07-106.18%), and 103.07% (90% CI: 100.21-106.01%), respectively. The 90% CI values for Cmax, AUC0-t, and AUC0-inf fell within the accepted range of bioequivalence (80.00-125.0%). Common adverse events included hypoglycemia, heart rate increase, palpitation, sweating, dizziness, and diarrhea. CONCLUSIONS: The test formulation (0.12 g) met the CFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated by healthy Chinese subjects. TRIAL REGISTRATION: This trial has been registered in the Chinese Clinical trial registry (ChiCTR2000030694), March 10, 2020.

Application of the 3Rs principles in the development of pharmaceutical generics.

Although the 3Rs are broadly applied in nonclinical testing, a better appreciation of the 3Rs is needed in the field of differentiated or value-added pharmaceutical generics because the minor changes in formulation, dosage form, indication, and application route often do not require additional safety testing. The US FDA and the EU EMA have comprehensive regulations for such drugs based on quality, therapeutic equivalence, and safety guidelines. However, no scientific publications on how the concept of replacement and reduction from 3Rs principles can be applied in the safety assessment of differentiated generics were found in the public domain. In this review, we discuss the application of 3Rs in nonclinical testing requirements for differentiated generics. Practical examples are provided in the form of case studies from regulated markets. We highlight the need for utilization of existing data to establish equivalence (differentiated generic vs innovator) in efficacy and safety. The case studies indicate that data requirements from animal experiments have been reduced to a large extent in some major markets without compromising quality and safety. In this context, we also highlight the problem that on a global scale, a true reduction of animal experiments will only be achieved when all countries adopt similar practices.

Understanding authorized generics-A review of the published clinical data.

WHAT IS KNOWN AND OBJECTIVES: Despite the large body of evidence demonstrating equivalent efficacy and safety for branded drugs and their generic counterparts, some patients and providers have the perception that generics may be less safe and effective than branded agents. Authorized generics (AGs) are a category of generic drugs defined by the United States Food and Drug Administration (FDA) as being the same as the brand-name drug without the brand's name on the label and which may have minor differences, such as tablet or capsule markings for identification. Studies in which AGs are considered along with other generics may increase our understanding of factors that may influence perceptions about generics and shed light on areas where education may be impactful. The objectives of this paper are to provide information about AGs, review studies in which they have been evaluated and explore the role that AGs may fill in the individualized treatment of patients. METHODS: A literature review was conducted on 30 September 2019 with follow-up search on 4 March 2020. The search was focussed on published papers and meeting abstracts that provided information on AGs with respect to medical and health outcomes of therapy as well as switching in individuals receiving branded, AG, or other generic agents. Information about patients' perceptions of generic medications and adherence to therapy was also included. Additional information, including relevant government sources, such as the FDA website and the Federal Trade Commission Report, was included as appropriate. RESULTS: The literature specific to AGs is limited, but available data clearly highlight the importance of patient perception of generics as well as medication appearance as factors that may affect adherence and potentially more frequent switchbacks to branded agents from generics or AGs. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first narrative review to provide a summary of the published evidence about AGs with respect to clinical and health outcomes and switching. There is a need for more research and education regarding the use of AGs in clinical practice if they are to become more recognized as a potential treatment choice for patients. Generic medications play an important role in the healthcare system, and AGs may be able to provide an option to meet the specific needs of individual patients.

Switch from branded to generic imatinib: impact on molecular responses and safety in chronic-phase chronic myeloid leukemia patients.

Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1-16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4-22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4-4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects.

Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck.

PURPOSE: Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products. METHODS: For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability. RESULTS: Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences. CONCLUSIONS: Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products. Graphical abstract.

Real-World Evaluation of Dosing in Patients Converted From Insulin Glargine (Lantus) to Insulin Glargine (Basaglar).

Background: Basaglar, insulin glargine (BGlar; Eli Lilly, Indianapolis, IN), a follow-on biologic, was developed after the patent for Lantus, insulin glargine (LGlar; Sanofi-Aventis, Paris, France) expired. Objective: To compare the dosing and hemoglobin A1C (A1C)-lowering effects of BGlar compared with LGlar in a real-world setting. Methods: Adult patients, at 5 clinics, with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) who were converted from LGlar to BGlar were included in this retrospective observational study. The primary outcome compared mean basal insulin dose (U/d) from the date of conversion to 6 months. Basal insulin and total daily insulin doses were also compared from baseline to 3- and 12-months postconversion, as also change in A1C, body weight, and estimated monthly acquisition costs of basal insulin. Results: Of the 225 patients included, 56% were male, and 81% had T2DM. The mean conversion dose (U/d) of LGlar was 46.3 ± 32.7. There was no significant difference in the mean BGlar dose (U/d) at 6 months (45.9 ± 33.5; P = 0.52), nor was there a statistical difference at 3 or 12 months. There were no significant differences in change in A1C at any time point. The estimated monthly acquisition cost of BGlar was significantly less than that for LGlar at conversion ($286 vs $341, P < 0.001) and 6 months ($290 vs $351, P < 0.001) respectively. Conclusion/Relevance: The results of this retrospective study suggest that BGlar resulted in similar glycemic outcomes compared with LGlar in a real-world setting and may be a preferable option in a value-based health care environment.

The impact of generic aromatase inhibitors on initiation, adherence, and persistence among women with breast cancer: Applying multi-state models to understand the dynamics of adherence.

PURPOSE: Clinical trials have clearly documented the survival benefit of aromatase inhibitors (AIs); however, many women fail to initiate (primary nonadherence) or remain adherent to AIs (secondary nonadherence). Prior studies have found that costs impact secondary nonadherence to medications but have failed to examine primary nonadherence. The purpose of this study is to examine primary and secondary adherence following the reduction in copays due to the introduction of generic AIs. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified 50 054 women diagnosed with incident breast cancer between 2008 and 2013. We compare women whose copays would change and those whose would not, due to the receipt of cost-sharing subsidies before and after generics were introduced using a difference-in-difference (DinD) analysis. To examine primary and secondary nonadherence, we rely on a multistate model with four states (Not yet initiated, User, Not Using, and Death). We adjusted for baseline factors using inverse probability treatment weights and then simulated adherence for 36 months following diagnosis. RESULTS: The generic introduction of AIs resulted in patients initiating AIs faster (DinD = -4.7%, 95%CI = -7.0, -2.3; patients not yet initiating treatment at 6-months), being more adherent (DinD ranging in absolute increase of 8.1%-10.4%) and being less likely to not be using the therapy (DinD range in absolute decrease of 1.2% at 6 months to 8.8% at 24 months) for women that do not receive a subsidy after generics were available. CONCLUSIONS: Introduction of generic alternatives to AIs significantly reduced primary and secondary nonadherence.

Bioequivalence of two tacrolimus 1-mg formulations under fasting conditions in healthy subjects: A randomized, two-period crossover trial
.

OBJECTIVE: The present study compared the pharmacokinetics of two (1 mg) tacrolimus formulations (test (generic from Panacea) and reference (innovator from Astellas)) after a single-dose administration as per the European Medicine Agency (EMA) guidelines to grant marketing authorization. MATERIALS AND METHODS: This study was a randomized, open-label, balanced, two-treatment, two-period, two-sequences, single-dose, truncated-area, crossover design with a washout period of 19 days between the phases. Healthy subjects aged 18 - 45 years (both inclusive) were included. Eligible subjects received a single oral dose of 5 × 1-mg capsule of tacrolimus either test or reference formulation. Blood samples were collected until 72.00 hours postdose, and peak concentration (Cmax) and area under the curve (AUC0-72) were evaluated in whole blood using validated LC-MS/MS. Safety was also assessed in each period. RESULTS: Of 56 subjects enrolled, 52 completed both study periods. The arithmetic mean (SD) Cmax for the reference and test formulations was 40.62 (11.30) and 46.20 (10.73) ng/mL, and AUC0-72 was 348.34 (156.41) and 361.04 (158.71) ng×h/mL, respectively. The geometric least square mean ratio (90% confidence interval (CI)) was 115.07% (90% CI: 109.81, 120.59) for Cmax and 103.78 (90% CI: 97.40, 110.58) for AUC0-72, which fell within the acceptance range as per EMA guidelines for narrow therapeutic index drugs (Cmax: 80.00 - 125.00%; AUC: 90.00 - 111.11%). No serious adverse event was observed. CONCLUSION: The generic tacrolimus was bioequivalent to the reference formulation, was well tolerated, and provides a well-acceptable alternative to the reference drug. Switching treatment to generic tacrolimus medication may reduce the cost and economic burden of treating transplanted patients.

Drug switching in the Netherlands: a cohort study of 20 active substances.

BACKGROUND: For a patient, drug switches are not desirable (either between a brand-name drug and a generic drug, or between two generic drugs of the same active substance). Research into the causes of drug switches, and related adverse drug reactions, is hampered by the absence of quantitative data on drug switches. METHODS: We describe the frequency of drug switches in the Netherlands for a selection of active substances. A retrospective cohort study was conducted using the Drug Information System of the National Health Care Institute in the Netherlands. We studied the Dutch patient population from mid-2009 to 2016. The selection of active substances (n = 20) was made based on a report by Lareb, the Netherlands Pharmacovigilance Centre, on adverse drug reactions related to drug switching, and we used qualitative and quantitative descriptive analyses. A drug switch is defined as the replacement of a patient's prescribed drug with a similar drug from a different manufacturer. RESULTS: We identified 23.8 million drug switches on a total of 206 million (11.6%) similar drug dispenses. The frequency of drug switches demonstrated a yearly peak in the period from January to March. In some months, for atorvastatin, losartan, pantoprazole, and irbesartan, more than 60% of similar drug dispenses were drug switches. Most drug switches (80.3%) were between two generic drugs, and 0.12% of these involved a drug from a European parallel import. The proportion of drug switches between two brand-name drugs decreased from 14.5 to 5.53% during our study period, and of these, 86.5% involved a drug from a European parallel import. CONCLUSIONS: Drug switching is common in the Netherlands, and most of the drug switches we studied are between generic drugs. The observed annual peak of drug switches is most likely explained by a specific Dutch reimbursement policy. Not only are the data valuable as is, but they also serve as a first step towards elucidating the reasons for the occurrence of these drug switches. In addition, these data can be used to put into perspective the adverse drug reactions associated with drug switching.

Were it business opportunities or hidden risks: Observations on clinical trials and marketing authorizations of Gilead Science's remdesivir in China.

New drugs against the in COVID-19 pandemic are urgently needed. Gilead Science's remdesivir has been introduced to China through special approval procedures, and was directly conducting the Phase III clinical trial. As expected, the marketing authorization process was completed soon. The drug brought hope to patients as well as business opportunities to companies. However, we must pay attention to the patent competition, generic drug competition and other unfair competition that remdesivir may face in China. China also needs to strengthen the innovation ability and international cooperation ability of local pharmaceutical companies by taking advantages of the opportunity to introduce remdesivir.

Tolerability and effectiveness of generic direct-acting antiviral drugs in eradication of hepatitis C genotype 4 among Egyptian patients.

BACKGROUND: We investigated tolerability and effectiveness of generic, less expensive direct antiviral drugs in the treatment of hepatitis C virus genotype 4 (HCV GT-4) in an Egyptian cohort. PATIENTS AND METHODS: Retrospectively, we analysed data from 648 patients with HCV GT4 attending Alexandria Main University Hospital from January 2016 to May 2017 [488 treatment naïve/160 treatment-experienced/288 with chronic hepatitis/360 with cirrhosis]. Patients received generic sofosbuvir/ledipasvir (n = 168, treatment naïve = 136, treatment-experienced = 32) or sofosbuvir/daclatasvir (n = 480, treatment naïve = 352, treatment-experienced = 128) ± ribavirin. We assessed sustained virologic response 12 weeks after treatment, non-response, relapse, treatment discontinuation and drug adverse reactions. RESULTS: An overall sustained virologic response 12 weeks after treatment was achieved in 97.8%, non-response in 0.6%, relapse in 0.3% and discontinuation of treatment in 1.3% of patients. Sofosbuvir/ledipasvir ± ribavirin regimen attained an overall sustained virologic response 12 weeks after treatment in 96.4% of patients (100% of treatment-experienced vs 95.6% of treatment naïve, P = 0.28), vs 98.3% for sofosbuvir/daclatasvir ± ribavirin regimen (100% of treatment-experienced vs 97.7% of treatment naïve, P = 0.08). No severe drug adverse events or deaths were reported except anaemia due to ribavirin. CONCLUSION: Generic direct antiviral drugs used in treating Egyptian patients with HCV GT-4 demonstrated equal potency, safety and tolerability compared to original brands, with low cost which would help to provide treatment to a larger scale of patients.

Clinical and pharmacokinetics equivalence of multiple doses of levodopa benserazide generic formulation vs the originator (Madopar).

AIMS: While several generic preparations of levodopa/carbidopa and levodopa/benserazide (LBD) are currently available, pharmacokinetic (PK) equivalence and therapeutic equivalence studies with levodopa generics are not available in Italy. Lack of data on generic formulations is a critical factor for their limited use in this country and often lead patients to refuse the generic version of the branded drug. METHODS: An experimental, 2-centre, randomized, double-blind, 2-sequence, noninferiority cross-over study was designed to evaluate both the PK equivalence and clinical equivalence of multiple doses of the generic preparation of LDB, Teva Italia, compared to the originator (Madopar). Forty-three out-patients with a diagnosis of idiopathic Parkinson's disease on LDB, were recruited and randomly assigned to 1 of 2 study sequences: generic-originator or originator-generic. Clinical evaluations were performed at the end of each study period. A PK study with an LDB fixed dose (100 + 25 mg) was performed in a subpopulation of 14 subjects. RESULTS: Clinical data showed a reduction of 0.49 and 1.54 in the mean UPDRS III scores for the LDB and the originator, respectively. The 95% CIs [-2.21: 0.11] of the mean difference original vs LDB are smaller than the clinically significant difference of 3 UPDRS III points, supporting the conclusion that the treatment with LDB is not inferior to the originator. No statistically significant differences were found with respect to area under the curve to last dose, half-life, maximum concentration, time to maximum concentration and last observed concentration. CONCLUSION: These findings prove the therapeutic clinical equivalence as well the PK equivalence of the generic LDB and the originator (Madopar).