About

Rodrigo Cristofoletti, Ph.D., joined the University of Florida in 2019 as a research assistant professor in the Department of Pharmaceutics within the College of Pharmacy. He holds a B.S. in Pharmaceutical Sciences from the University of Sao Paulo, Brazil, obtained in 2004, and earned his Ph.D. summa cum laude from Johann Wolfgang Goethe University in Frankfurt am Main, Germany, in 2017 under the supervision of Dr. Jennifer Dressman. His professional experience includes 15 years at the Clinical Pharmacology & Biopharmaceutics Office of the Brazilian Drug Regulatory Agency (ANVISA), where his research on oral drug absorption contributed to the development of scientific foundations for generic policies in Brazil. Dr. Cristofoletti's research focuses on integrating in vitro systems with quantitative modeling to inform drug discovery and development, emphasizing mechanistic absorption models, drug-drug interactions, and disease-based models. His lab applies stem cell technology, co-culture techniques, and microfluidics to develop microphysiological systems, including segment-specific intestine-on-a-chip models to study drug absorption, membrane integrity, and transport-mediated kinetics. He is also interested in organ-on-a-chip technology to investigate drug penetration in brain tissue. Dr. Cristofoletti has published over 50 peer-reviewed articles and 5 book chapters, and he serves as a member of the Special Interest Group on BCS and Biowaiver of the International Pharmaceutical Federation (FIP) and the Brazilian Pharmacopoeia.

Research topics

• Computer Science
• Pharmacology
• Medicine
• Chemistry
• Mathematics
• Biochemical engineering
• Engineering
• Statistics
• Econometrics
• Biotechnology

Selected publications

• Bench to bedside modelling of mRNA encoding IgG using a multiscale mechanistic PK-PD model: A case study with anti-claudin 18.2

  2026-01-01

  articleOpen accessSenior author

  <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d621355e60"> <b>Objectives:</b> Messenger RNA (mRNA) therapeutics encoding monoclonal antibodies offer a novel platform for in vivo protein expression. However, quantitative translation from preclinical to clinical systems remains a major hurdle due to complex multi-compartmental processes including nanoparticle delivery, cellular uptake, mRNA translation, and target binding. This study aimed to develop and apply a multiscale mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to characterize and predict the in vivo behavior of an mRNA therapeutic encoding an anti-claudin 18.2 IgG, from pre-clinical models to human predictions. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d621355e65"> <b>Methods:</b> We developed a multiscale mechanistic model capturing key processes: (i) LNP-mediated delivery and endocytosis via LDLR pathways, (ii) endosomal escape and mRNA release, (iii) cytoplasmic mRNA translation into IgG, (iv) IgG systemic distribution and target binding, and (v) transient increase in cytokines because of exogenous mRNA. Model development was grounded in published in-vitro, mouse and NHP PK-PD data[ <a class="xref-link" href="#r1">1</a>]. Allometric scaling principles and literature-informed differences in LDLR expression and endocytosis kinetics were used for human translation. The model was calibrated using Monolix 2023R1. Sensitivity analysis identified key translational bottlenecks. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d621355e73"> <b>Results:</b> The model adequately captured the time course of mRNA, expressed IgG, and transient increase in cytokines in mice and NHP following intravenous mRNA administration. The rate of degradation of IgG was 2.87 1/h (4.28% RSE), The rate of endosomal escape was 231 1/h (10.9% RSE), the rate of degradation of mRNA was 0.114 1/h (6.2% RSE) for mouse and NHP when fitted simultaneously. All the physiological volumes were fixed from literature[ <a class="xref-link" href="#r2">2</a>]. Increase of cytokines in plasma was characterized by using transit compartment model in which Emax was 2390 (2.68%), EC50 was 15 ng/mL (1.85% RSE) and tau was 2.43 1/h (0.93% RSE). The model was able to simulate the %Receptor Occupancy and plasma PK in humans based on the simulations 0.025 mg/kg was selected for the starting dose for first-in-human dose. Sensitivity analysis revealed that degradation of IgG and mRNA were critical determinants of interspecies translation. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d621355e81"> <b>Conclusions:</b> This study presents a comprehensive multiscale PK-PD framework to characterize and predict the behavior of mRNA-encoded therapeutic antibodies from preclinical systems to humans. Application to an anti-claudin 18.2 IgG mRNA therapy highlighted species-specific differences in nanoparticle processing and translation kinetics, providing a rational basis for dose selection in early clinical trials. This modeling framework can be extended to other mRNA-based protein therapeutics to improve translational predictability and accelerate clinical development[ <a class="xref-link" href="#r3">3</a>].

  PublisherDOI

• Translational two-pore PBPK model to characterize whole-body disposition of different-size oligonucleotide therapeutics

  2026-01-01

  articleOpen accessSenior author

  <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d632258e62"> <b>Objectives:</b> The pharmacokinetics (PK) of oligonucleotide therapeutics are governed by complex processes such as size-dependent tissue extravasation, renal clearance, and intracellular trafficking. While existing physiologically based pharmacokinetic (PBPK) models have advanced our understanding of oligonucleotide disposition, most are limited in either molecular diversity, scope of biological mechanisms, or interspecies translation. To address these limitations, we aimed to develop and optimize a mechanistic, translational two-pore PBPK model that accounts for molecular weight (MW)-dependent distribution and clearance pathways for oligonucleotides, enabling prediction of systemic and tissue exposures across preclinical species and humans. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d632258e67"> <b>Methods:</b> A whole-body PBPK model incorporating two-pore formalism was constructed and parameterized to describe both convective and diffusive transport across vascular endothelium based on oligonucleotide size and physicochemical properties. The model includes size-dependent renal clearance, endosomal recycling where applicable (e.g., for GalNAc-conjugated oligonucleotides), and lysosomal degradation. A diverse dataset—including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), was curated across four species: mice, rats, monkeys, and humans. Tissue-specific physiological parameters were adapted for each species, and model calibration was performed using plasma and tissue PK profiles with literature-sourced data[ <a class="xref-link" href="#r1">1</a>],[ <a class="xref-link" href="#r2">2</a>],[ <a class="xref-link" href="#r3">3</a>],[ <a class="xref-link" href="#r4">4</a>]. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d632258e84"> <b>Results:</b> The developed PBPK model accurately recapitulates the plasma and tissue disposition of oligonucleotides ranging in molecular weight from ~6 to 20 kDa. Predicted area under the curve (AUC) values for most oligonucleotides were within a two-fold error compared to observed data[ <a class="xref-link" href="#r5">5</a>],[ <a class="xref-link" href="#r6">6</a>]. The model captured key features of oligonucleotide pharmacokinetics, including rapid systemic clearance for smaller, unmodified species, and prolonged circulation for larger or conjugated molecules. Sensitivity analyses identified molecular weight, charge, and chemical modification as primary drivers of extravasation and clearance. The model also quantitatively characterized contributions of filtration, lysosomal degradation, endonucleases metabolism, and endosomal recycling to overall elimination. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d632258e95"> <b>Conclusions:</b> We present a cross-species, cross-modality PBPK model that enables quantitative prediction of oligonucleotide pharmacokinetics across a range molecular size. By incorporating mechanistic insights into size-dependent transport and clearance, the model provides a platform to support rational design, species translation, and dose selection for oligonucleotide therapeutics. This framework lays the foundation for integrating additional complexities such as characterization of different structural asymmetries, and intracellular pharmacodynamics in future iterations.

  PublisherDOI

• Translational Model to Predict Lung and Prostate Distribution of Levofloxacin in Humans

  Pharmaceutics · 2026-01-13

  articleOpen accessCorresponding

  Background/Objectives: Levofloxacin (LVX) is a fluoroquinolone approved for the treatment of bacterial pneumonia, sinusitis, and prostatitis. Emerging in vitro and preclinical evidence suggests that efflux transporters are involved in LVX’s target tissue site distribution. Methods: The objective of this research was to characterize tissue exposure using a physiologically based pharmacokinetic (PBPK) model to be able to make more educated choices for optimal doses using target site pharmacokinetics data. Results: The final PBPK model in humans was applied to simulate free target site concentrations of LVX in lung and prostate, linking to minimum inhibitory concentrations (MIC) to assess appropriateness of currently approved dosing regimens for infections in both tissues. The clinical PBPK model was able to reproduce total plasma as well as free lung and prostate exposure of LVX in humans. Efflux transporters participate in LVX distribution to prostatic but not pulmonary tissue. Our results show a good penetration of LVX in both tissues with unbound partition coefficient (Kp,uu) equal to 0.79 and 0.72 for lung and prostate, respectively. Since LVX penetration in lung and prostate is similar, different sensitivities of the pathogens to LVX will dictate the effectiveness of the approved therapeutic regimen in the treatment of bacterial pneumonia, sinusitis, and prostatitis. Conclusions: Our research provides relevant insight into LVX’s target site exposure in lung and prostate. When integrated with pathogen-specific susceptibility data, these findings can be applied to refine current dosing regimens and help optimize the pharmacological treatment outcomes.

  PublisherOA PDFDOI

• Biowaiver monograph for immediate-release solid oral dosage forms: Empagliflozin

  Journal of Pharmaceutical Sciences · 2025-10-09 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Brazil

  AAPS advances in the pharmaceutical sciences series · 2025-01-01

  book-chapter
  PublisherDOI

• A physiologically based biopharmaceutics modeling (PBBM) framework for characterizing formulation-dependent food effects: Paving the road towards fed state virtual BE studies for itraconazole amorphous solid dispersions

  European Journal of Pharmaceutical Sciences · 2025-02-19 · 7 citations

  articleOpen accessSenior authorCorresponding

  This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted and fed state conditions, exploring the potential of PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected to extensive in vitro biopharmaceutical testing, including solubility studies and dissolution tests under fasted and fed state conditions, revealing significant differences in dissolution behaviors between Sempera® and Tolsura®. The impact of food and hypochlorhydria on drug absorption was evaluated using a stepwise mechanistic deconvolution-reconvolution PBBM approach, integrating fundamental parameters based on the in vitro data into the final model. Our model not only successfully predicted the effects of acid reducing agents (ARA) and food on the oral absorption of ITRA, but also captured the between-subject variability, demonstrating the utility of this approach in understanding the complex interplay between drug, formulation, and gastrointestinal environment. Most importantly, the PBBM was able to accurately predict the positive impact of food on the absorption of Sempera® and the negative food effect of Tolsura®. The findings highlight the importance of considering formulation characteristics and gastrointestinal physiology, underscoring the potential of PBBM in bioequivalence (BE) assessment of generic formulations under varying physiological conditions, including in the fed state and in hypochlorhydric patients. The successful application of this stepwise and mechanistic PBBM approach suggests a potential pathway for streamlining drug development and may contribute to more informed decision-making for BE assessment.

  PublisherDOI

• Bench to Bedside Modeling of <scp>mRNA</scp> Encoding <scp>IgG</scp> Using a Multiscale Mechanistic Pharmacokinetic‐Toxicokinetic ( <scp>PK</scp> ‐ <scp>TK</scp> ) Model: A Case Study With Anti‐Claudin 18.2

  Clinical and Translational Science · 2025-09-01

  articleOpen accessSenior authorCorresponding

  In vivo expression of mRNA-encoded antibodies offers a novel platform for targeted therapies. However, translating preclinical findings to clinical applications remains challenging due to complex processes, including nanoparticle delivery, cellular uptake, mRNA translation, and target binding. This study developed a multiscale mechanistic pharmacokinetic-toxicokinetic (PK-TK) model to characterize and predict the in vivo behavior of an mRNA therapeutic encoding an anti-claudin 18.2 IgG, scaling from preclinical models to human predictions. The model integrates key processes: (i) lipid nanoparticle (LNP)-mediated delivery and endocytosis via low-density lipoprotein receptors (LDLR), (ii) endosomal escape and mRNA release, (iii) cytoplasmic mRNA translation into IgG, (iv) IgG systemic distribution and target binding, and (v) transient cytokine elevation triggered by exogenous mRNA. Model development leveraged published in vitro and in vivo data from mice, rats, and non-human primates (NHPs). Allometric scaling principles and inter-species differences in LDLR expression enabled human translation. Sensitivity analysis identified critical translational bottlenecks. The model successfully recapitulated the time course of mRNA, expressed IgG, and cytokine/chemokine levels in mice following intravenous administration. For human predictions, simulations of receptor occupancy and systemic exposure of encoded antibody informed the selection of 0.01 mg/kg as the starting dose for first-in-human trials. By highlighting species-specific differences in nanoparticle processing and mRNA translation kinetics, this framework provides a rational basis for dose selection. Applicable to other mRNA-based protein therapeutics, this multiscale PK-TK model enhances translational predictability, streamlining clinical development.

  PublisherOA PDFDOI

• Physiologically Based Pharmacokinetic Modeling of Clobazam and Stiripentol Co-Therapy in Dravet Syndrome

  Journal of Personalized Medicine · 2025-11-11 · 1 citations

  articleOpen accessSenior authorCorresponding

  Background: Dravet syndrome, a severe early-onset epileptic encephalopathy, is treated with multiple antiepileptic drugs such as clobazam (CLB) and stiripentol (STP), increasing the risk of drug–drug interactions (DDIs). Given the limited pediatric pharmacokinetic data, this study developed physiologically based pharmacokinetic (PBPK) models for CLB and STP to optimize dosing and assess DDI risk across pediatric age groups. Methods: We developed PBPK models for CLB, its active metabolite, N-desmethylclobazam (N-CLB), and STP in healthy adults and pediatric patients with Dravet syndrome aged two years and older. We evaluated the inhibitory effect of STP on CLB and N-CLB metabolism, accounting for CYP2C19 phenotypes. The model was extrapolated to predict drug exposure in pediatric patients under two years of age. Results: PBPK models for CLB, N-CLB, and STP successfully recapitulated observed pharmacokinetics in healthy adults and pediatric patients older than two years. Model verification against clinical DDI data showed that co-administration of STP with CLB resulted in a clinically insignificant increase in CLB exposure (Cmin ratio = 1.77). In contrast, N-CLB exposure increased approximately 7-fold in CYP2C19 extensive metabolizers (Cmin ratio ≈ 7) and slightly decreased in poor metabolizers (Cmin ratio = 0.9), consistent with the CYP2C19-dependent metabolism of N-CLB. Extrapolation to pediatric patients under two years of age predicted CLB, N-CLB, and STP exposures that were comparable to older children and remained within their reported efficacy and safety margins, suggesting no major ontogeny-related effect on exposure. Conclusions: The PBPK model supports the safe extrapolation of CLB and STP co-administration to pediatric Dravet syndrome patients as young as six months.

  PublisherOA PDFDOI

• Microphysiological Systems: Advancing Insights into Brain Development and Disorders

  IntechOpen eBooks · 2025-07-30

  book-chapterOpen access

  Cerebral organoids have transformed neuroscience, replicating key features of brain development to study neurodevelopmental, neuropsychiatric and neurodegenerative disorders. These models offer critical insights into human-specific processes and have been further enhanced by technologies like brain-on-a-chip platforms and multi-organ systems, enabling systemic disease modeling and advancing drug discovery. This chapter explores brain development from conception to adulthood, highlighting how microphysiological systems model healthy and diseased states. It begins by outlining neurodevelopmental milestones such as neural induction, progenitor differentiation, synaptic formation, and neuroplasticity as the brain evolves through childhood, adolescence, and adulthood. These processes establish the foundation for understanding disruptions leading to disorders. Brain organoids are emphasized as groundbreaking tools, offering unparalleled fidelity in studying conditions like Down’s syndrome, Leigh’s syndrome, autism spectrum disorders, and Alzheimer’s disease. These models address critical gaps in neuroscience, driving advances in drug discovery and therapeutic innovation. Emerging technologies, including microfluidic platforms, gene editing, and machine learning, expand the scope of organoid research, enabling investigations into complex interactions and biocomputing applications. Despite their promise, challenges in functional maturity, scalability, and ethical considerations persist. Overcoming these barriers will further enhance brain organoid research, paving the way for deeper insights into brain development and innovative treatments for neurological disorders.

  PublisherOA PDFDOI

• Assessing Impact of Food on Oral Drug Bioequivalence Supporting ICH M13 A with the Advancements of Physiologically Based Pharmacokinetic Modeling

  Pharmaceutical Research · 2025-05-01 · 3 citations

  article
  PublisherDOI

Frequent coauthors

• Jennifer B. Dressman

  Fraunhofer Institute for Translational Medicine and Pharmacology

  54 shared

• James E. Polli

  University of Maryland, Baltimore

  32 shared

• Vinod P. Shah

  University of the Potomac

  28 shared

• Bertil Abrahamsson

  AstraZeneca (Sweden)

  27 shared

• Peter Langguth

  Johannes Gutenberg University Mainz

  26 shared

• Stephan Schmidt

  University of Florida

  26 shared

• Joshua D. Brown

  Center for Drug Evaluation and Research

  21 shared

• Alan Parr

  Oncoceutics (United States)

  17 shared

Education

• B.S., Pharmaceutical Sciences

  University of Sao Paulo

  2004

• Ph.D.

  Johann Wolfgang Goethe University

  2017

Awards & honors

• Simcyp Academic Most Informative and Scientific Report 2017…