Rodrigo Cristofoletti

Agência Nacional de Vigilência Sanitária | ANVISA · Department of Bioequivalence

Reliable, experimentally determined partition coefficient P (logP) for most drugs are often unavailable in the literature. Many values are from in silico predictions and may not accurately reflect drug lipophilicity. In this study, a robust, viable, and resource sparing method to measure logP was developed using reverse phase high performance liqui...

Levonorgestrel (LNG) is a progestin used in many contraceptive formulations, including subcutaneous implants. There is an unmet need for developing long-acting formulations for LNG. To develop long-acting formulations, release functions need to be investigated for LNG implant. Therefore, a release model was developed and integrated into an LNG phys...

Pediatric drugs knowledge still leaves several gaps to be filled, all the while many biopharmaceutic properties applied to adults do not work in pediatrics. The solubility in many cases is extrapolated to pediatrics; however, sometimes it may not represent the real scenario. In this context, the aim of this study was to assess the possibility of th...

Roux-en-Y gastric bypass (RYGB) is one of the most common surgical treatments for obesity due to the effective long-term weight loss and remission of associated comorbidities. Carvedilol, a third-generation β-blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH-dependent solubility and dissolution, and h...

Introduction Ketoconazole and posaconazole are two weakly basic broad-spectrum antifungals classified as Biopharmaceutics Classification System class II drugs, indicating that they are highly permeable, but exhibit poor solubility. As a result, oral bioavailability and clinical efficacy can be impacted by the formulation performance in the gastroin...

Objective: To evaluate the association of concomitant topiramate and oral hormonal contraceptive use with unintended pregnancies. Study design: We conducted a retrospective cohort design in MarketScan Research Databases (2005-2018) on women aged 12-48 who had migraines or chronic headaches and concomitantly used topiramate and oral contraceptive...

This report summarizes the proceedings for Day 2 Sessions 1 and 3 of the 2‐day public workshop entitled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches”, a jointly sponsored workshop by U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG). The aims of this worksh...

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride...

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for...

Worldwide, 922 million women of reproductive age (or their partners) use some sort of contraception to prevent pregnancy. Oral combined hormonal contraceptives (CHC) typically utilize a combination of a progestin and an estrogen. CHC are potentially at risk to metabolic drug‐drug interaction (DDI) via CYP3A4, the main enzyme involved in the oxidati...

Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications holds great promise as modelling and simulation tool in the field of modern oral modified release (MR) products. Understanding of gastro-intestinal absorption related processes is crucial to ensure the successful development of complex oral drug generic products...

While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected deg...

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g. levonorgestrel, LNG) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug‐drug interactions (DDIs) and obesity (women with...

Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms contain...

Tramadol is an opioid medication used to treat moderately severe pain. CYP2D6 inhibition could be important for tramadol as it decreases the formation of its pharmacologically active metabolite, O‐desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and com...

Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population...

The exposure‐response relationship of direct acting oral anti‐coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PK) and thus s...

Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered “highly soluble”...

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin’s Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transp...

Levonorgestrel (LNG) is the active moiety in many hormonal contraceptive formulations. It is typically co‐formulated with ethinyl estradiol (EE) to decrease intermenstrual bleeding. Due to its widespread use and CYP3A4‐mediated metabolism, there is concern regarding drug‐drug interactions (DDI), particularly a sub‐optimal LNG exposure when co‐admin...

The authors make the following correction to this paper after the final publication of the work [1]: The authors acknowledge that Dr. Patrick Augustijns should have been included as one of the co-authors because of the conceptualization of the work with respect to the subject ‘real-life dosing conditions’. The Author Contributions section has been...

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory d...

The aims of the proposed study were to develop and verify a quantitative model-based framework to anticipate the in vivo bioequivalence of ibuprofen immediate release formulations. This stepwise approach integrated virtual bioequivalence trials to simulate the test to reference (T/R) ratio for positive (i.e., bioequivalent) and negative (i.e., non-...

In the present work, we explored if Coca-Cola® had a beneficial impact on the systemic outcome of the weakly basic drug loratadine (Wal-itin®, immediate-release formulation, 10 mg, generic drug product). To map the contribution of underlying physiological variables that may positively impact the intestinal absorption of loratadine, a multi-compartm...

In this monograph, literature data is reviewed to evaluate the feasibility of waiving in vivo bioequivalence (BE) testing and instead applying the Biopharmaceutics Classification System (BCS) based methods to the approval of immediate-release (IR) solid oral dosage forms containing moxifloxacin hydrochloride as the sole active pharmaceutical ingred...

Aim: The goal of this study is to present the utility of quantitative modeling for extrapolation of drug safety and efficacy to underrepresented populations in controlled clinical trials. To illustrate this, the stepwise development of an integrated disease/pharmacokinetics/pharmacodynamics model of antipyretic efficacy of ibuprofen in children wi...

Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release (IR) solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the FDA, WHO and...

Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of...

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver...

In the present study an in vitro-in vivo extrapolation of dissolution integrated to a physiologically-based pharmacokinetics modeling approach, considering a product-specific particle size distribution and a self-buffering effect of the drug, is introduced and appears to be a promising translational modeling strategy to support drug product develop...

The application of modeling and simulation (M&S) tools to biological, physiological, and clinical data has great potential to enhance drug development and regulatory decision making. The strategic development of multidisciplinary projects aimed at integrating methodologies from different disciplines may bridge between preclinical and clinical drug...

The objective of this research was to evaluate the impact of changes in the formulation of metoprolol extended‐release (ER) tablets on dissolution, pharmacokinetic, and exercise‐induced heart rate (EIHR) using a combined physiologically based absorption pharmacokinetic, and population pharmacokinetic/pharmacodynamic modeling and simulation approach...

This report provides a brief description of the 2018 RedIF Congress that took place in Guadalajara (Mexico), on November 7‐9. The meeting aimed to foster modeling & simulation approaches for drug development, regulatory sciences and clinical application in Latin America. Organizations that cosponsored the meeting were: University of Guadalajara, In...

Objectives The objective of this review was to provide an overview of pharmacokinetic/pharmacodynamic (PK/PD) models, focusing on drug‐specific PK/PD models and highlighting their value added in drug development and regulatory decision‐making. Key findings Many PK/PD models, with varying degrees of complexity and physiological understanding have b...

The growth in the utilization of systems thinking principles has created a paradigm shift in the regulatory sciences and drug product development. Instead of relying extensively on end product testing and one-size-fits-all regulatory criteria, this new paradigm has focused on building quality into the product by design as well as fostering the deve...

Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To clarify the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimal...

This chapter contains basically the same information as previously published [1]. Each law and/or regulation has been summarized more concisely. In addition, all new regulations approved after 2010 have been included, such as Resolution 37/11 and 27/12, dealing with biowaivers and bioanalytical method validation, respectively.

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the hig...

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index,...

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as...

Objective: Clinically relevant critical quality attributes (CQA's) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored. Significance: A simplified scoring system for the biopharmaceutics risk assessment roadmap (Bio...

Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to e...

In vitro–in vivo extrapolation techniques combined with physiologically based pharmacokinetic models represent a feasible approach to establishing links between critical quality attributes and the time course of drug concentrations in vivo. By further integrating the results with pharmacodynamic (PD) models, scientists can also explore the time cou...

The predictive capacity of in vitro dissolution tests using the Biopharmaceutics Classification System (BCS)-based experimental setup to anticipate in vivo bioequivalence outcomes for BCS class 2 weak acids has been questioned. In this work, the effect of buffer concentration media was investigated as a possible approach to ensuring the discriminat...

Background: The predictive capacity of in vitro dissolution tests using 50mM phosphate buffer at pH 6.8 to anticipate in vivo bioequivalence outcomes for highly permeable and poorly soluble weak acids has been questioned. In previous work, it was shown that using a lower buffer capacity could correctly distinguish the in vivo behavior of products...

Due to the higher total clearance of certain drugs in children than in adults, it is recommended that, in such cases, higher relative doses on a milligram/kilogram basis should be administered to children in order to achieve similar systemic exposure to adults. This is the case for fluconazole and ketoconazole. Even though the lower absorptive surf...

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System,...

The development of in vitro dissolution tests able to anticipate the in vivo fate of drug products has challenged pharmaceutical scientists over time, especially in the case of ionizable compounds. In the seminal model proposed by Mooney et al. thirty-five years ago, the pH at the solid-liquid interface (pH0) was identified as a key parameter in pr...

Ketoconazole and posaconazole are both Biopharmaceutics Classification System class 2 drugs (highly permeable, poorly soluble), are structurally similar, and are administered at the same doses. Nevertheless, the duodenal concentration profile and the magnitude of the positive food effect observed for these 2 drugs are markedly different. The aim of...

Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its ther...

The paediatric population undergoes developmental changes in gastric pH, gastric emptying, intestinal transit time, membrane permeability, protein binding, body water, distribution and metabolism. It is widely recognised that changes in these parameters may result in an alteration of the plasma profile and thus in key bioequivalence parameters such...

Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system...

ABSTRACT: Literature data pertaining to the decision to allow a waiver of in vivo bioequiv- alence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz’s permeability and its failure to compl...

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index,...

Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venturesome for different drugs. A PBPK model constructed with Simcyp Simulator® using reported biopharmaceutics parameters for ibuprofen was coupled with two publishe...

Estimation of metabolite data as a supportive evidence of comparable therapeutic outcome is recommended by various guidance documents. However, a consensus on using it solely to establish bioequivalence (BE) is lacking as parent drug is believed to detect pharmacokinetic differences between test and reference formulations better. Four BE studies of...

The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the “highly soluble” criteria according to World Health O...

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing bisoprolol as the sole active pharmaceutical ingredient (API) are reviewed. Bisoprolol is classified as a Class I API according to the current Biopharmaceutics Classification...

In the XIX and XX centuries, Latin American countries have experienced several changes on politics and economics, facing problems related to progress and growth, technological development, demographic transition, and the environment. In the 2010s this region presents a high level of health demands, which causes financial difficulties, especially in...

Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition clas...

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing stavudine (d4T) are reviewed. According to Biopharmaceutics Classification System (BCS), d4T can be assigned to BCS class I. No problems with BE of IR d4T formulations contai...

This study compared the antipyretic effects of ibuprofen and indomethacin regarding the efficacy in blocking fevers induced by lipopolysaccharide (LPS from E. coli) or pyrogenic mediators that act on prostaglandin (PG)-dependent and PG-independent pathways. The content of PGE2 in the cerebrospinal fluid (CSF) and the dependence on central arginine...

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levofloxacin as the only active pharmaceutical ingredient (API) are reviewed. According to the current Biopharmaceutics Classification System, levofloxacin can be assigned to...

It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET(B) receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, ind...