Interspecies Scaling Research Articles

Model-Based Interspecies Scaling for Predicting Human Pharmacokinetics of CB 4332, a Complement Factor I Protein

Interspecies scaling of the pharmacokinetics (PK) of CB 4332, a 150 kDa recombinant complement factor I protein, was performed using traditional and model-based approaches to inform first-in-human dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous and subcutaneous (SC) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modeling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. The traditional dose-by-factor approach calculated a maximum recommended starting SC dose of 0.9 mg/kg once weekly, which was predicted it to result in a trough steady-state concentration lower than the determined efficacy target range for CB 4332 in humans. Model simulations predicted the efficacy target range to be reached using 5 mg/kg once weekly SC dosing.

Inter-Species Pharmacokinetic Modeling and Scaling for Drug Repurposing of Pyronaridine and Artesunate.

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.

Unveiling human vulnerability and a new interspecies scaling law for brain injury under blast loading

The common belief that animals with larger heads are more tolerated to brain injury faces challenges under the extreme conditions of blast loading. Recent studies indicate that humans, who have notably larger heads than other species of similar body weight, exhibit a unique vulnerability. Integrating animal experimental data, advanced head modeling, and pressure propagation theories, this research elucidates the injury mechanisms across species as the blast wave transitions from the extremely hard skull to the extremely soft brain. We propose a new interspecies scaling law based on consistent peaks of intracranial pressure, rather than head size, to redefine the translation from animal exposure thresholds to human risk assessment. This shift in perspective underscores the imperative to comprehensively consider both head geometry and size in predicting tolerance to blast brain injury, moving beyond simplistic size-based comparisons. Our study's insights contribute significantly to redefining injury risk models and fostering innovative prevention strategies against blast-induced traumatic brain injury (bTBI).

Human and Porcine Lumbar Endplate Injury Risk in Repeated Flexion-Compression.

Low back pain (LBP) affects 50-80% of adults at some pointin their lifetime, yet the etiology of injury is not well understood. Those exposed to repeated flexion-compression are at a higher risk for LBP, such as helicopter pilots and motor vehicle operators. Animal injury models offer insight into in vivo injury mechanisms, but interspecies scaling is needed to relate animal results to human. Human (n = 16) and porcine (n = 20) lumbar functional spinal units (FSUs) were loaded in repeated flexion-compression (1Hz) to determine endplate fracture risk over long loading exposures. Flexion oscillated from 0 to 6° and peak applied compressivestress ranged from 0.65 to 2.38MPa for human and 0.64 to 4.68MPa for porcine specimens. Five human and twelve porcine injuries were observed. The confidence intervals for human and porcine 50% injury risk curves in terms of stress and cycles overlapped, indicating similar failure behavior for this loading configuration. However, porcine specimens were more tolerant to the applied loading compared to human, demonstrated by a longer time-to-failure for the same applied stress. Optimization revealed that time-to-failure in human specimens was approximately 25% that of porcine specimens at a given applied stress within 0.65-2.38MPa. This study determined human and porcine lumbar endplate fracture risks in long-duration repeated flexion-compression that can be directly used for future equipment and vehicle design, injury prediction models, and safety standards. The interspecies scale factor produced in this study can be used for previous and future porcine lumbar injury studies to scale results to relevant human injury.

Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs.

Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood-brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (F ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5mg/m2 in the first-in-human dose escalation study.

Scaling approaches for the prediction of human clearance of LNA-i-mir-221: A retrospective validation

LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2.

Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.

The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^-0.25 (AS by W^-0.25) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.

Uptake Transporters at the Blood-Brain Barrier and Their Role in Brain Drug Disposition.

Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to preclinical to clinical translation. These transporters are members of the solute carrier (SLC) superfamily, which includes organic anion transporter polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), and amino acid transporters. In this systematic review, we provide an overview of the current knowledge of uptake drug transporters in the brain and their contribution to drug disposition. Here, we also assemble currently available proteomics-based expression levels of uptake transporters in the human brain and their application in translational drug development. Proteomics data suggest that in association with efflux transporters, uptake drug transporters present at the BBB play a significant role in brain drug disposition. It is noteworthy that a significant level of species differences in uptake drug transporters activity exists, and this may contribute toward a disconnect in inter-species scaling. Taken together, uptake drug transporters at the BBB could play a significant role in pharmacokinetics (PK) and pharmacodynamics (PD). Continuous research is crucial for advancing our understanding of active uptake across the BBB.

Interspecies scaling of toxicity reference values in human health versus ecological risk assessments: A critical review.

Risk assessments that focus on anthropogenic chemicals in environmental media-whether considering human health or ecological effects-often rely on toxicity data from experimentally studied species to estimate safe exposures for species that lack similar data. Current default extrapolation approaches used in both human health risk assessments and ecological risk assessments (ERAs) account for differences in body weight between the test organisms and the species of interest, but the two default approaches differ in important ways. Human health risk assessments currently employ a default based on body weight raised to the three-quarters power. Ecological risk assessments for wildlife (i.e., mammals and birds) are typically based directly on body weight, as measured in the test organism and receptor species. This review describes differences in the experimental data underlying these default practices and discusses the many factors that affect interspecies variability in chemical exposures. The interplay of these different factors can lead to substantial departures from default expectations. Alternative methodologies for conducting more accurate interspecies extrapolations in ERAs for wildlife are discussed, including tissue-based toxicity reference values, physiologically based toxicokinetic and/or toxicodynamic modeling, chemical read-across, and a system of categorical defaults based on route of exposure and toxic mode of action. Integr Environ Assess Manag 2024;20:749-764. © 2023 SETAC.

Novel modeling approach integrating population pharmacokinetics and interspecies scaling to predict human pharmacokinetics of the new anti-tuberculosis agent telacebec (Q203)

Telacebec is a new anti-tuberculosis agent with promising therapeutic activity and a favorable safety profile. This study aimed to characterize the pharmacokinetics of telacebec via interspecies scaling and population pharmacokinetic modeling for the prediction of human pharmacokinetics. Preclinical pharmacokinetic data were obtained from mice, rats, and dogs following intravenous and oral doses of telacebec. A population pharmacokinetic model was developed to describe the pharmacokinetic data from all three species. The disposition parameters were well correlated with the body weight for all species using an allometric equation. Thus, the allometric scaling was incorporated into the population pharmacokinetic model, which could simultaneously describe the plasma concentration vs. time data from all preclinical studies as well as the Phase 1A clinical study. The developed model was used to predict the pharmacokinetics of telacebec after IV injection, including the clearance (CL) of 168.58 [118.86 – 238.73] mL/min and volume of distribution (Vss) of 968.84 [396.87 – 2831.31] L for 80-kg human. The absolute bioavailability of telacebec in humans in the fed state was estimated as 70.34 ± 9.91%. Finally, the population pharmacokinetic model with allometric scaling was utilized to simulate the plasma concentration vs. time profiles of telacebec after multiple oral doses in humans. The model-predicted profiles well agreed with the observed data in Phase 1B clinical trial. The present pharmacokinetic model may help better understand the activity of telacebec, leading to the design of optimal dosing regimens and new formulation development.

Quantitative intravitreal pharmacokinetics in mouse as a step towards inter-species translation

Although mouse models are widely used in retinal drug development, pharmacokinetics in mouse eye is poorly understood. In this study, we applied non-invasive in vivo fluorophotometry to study pharmacokinetics of intravitreal fluorescein sodium (molecular weight 0.38 kDa) and fluorescein isothiocyanate–dextran (FD-150; molecular weight 150 kDa) in mice. Intravitreal half-lives of fluorescein and FD-150 in mouse eyes were 0.53 ± 0.06 h and 2.61 ± 0.86 h, respectively. These values are 8–230 times shorter than the elimination half-lives of similar compounds in the human vitreous. The apparent volumes of distribution in the mouse vitreous were close to the anatomical volume of the mouse vitreous (FD-150, 5.1 μl; fluorescein, 9.6 μl). Dose scaling factors were calculated from mouse to rat, rabbit, monkey and human translation. Based on pharmacokinetic modelling and compound concentrations in the vitreous and anterior chamber, fluorescein is mainly eliminated posteriorly across blood-retina barrier, but FD-150 is cleared via aqueous humour outflow. The results of this study improve the knowledge of intravitreal pharmacokinetics in mouse and facilitate inter-species scaling in ocular drug development.

Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study

BackgroundWe developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation.MethodsIn this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0–2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33).ResultsSeventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3–4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose.ConclusionsThe excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).

Evaluation of a Cardiovascular Systems Model for Design and Analysis of Hemodynamic Safety Studies.

Early prediction, quantification and translation of cardiovascular hemodynamic drug effects is essential in pre-clinical drug development. In this study, a novel hemodynamic cardiovascular systems (CVS) model was developed to support these goals. The model consisted of distinct system- and drug-specific parameter, and uses data for heart rate (HR), cardiac output (CO), and mean atrial pressure (MAP) to infer drug mode-of-action (MoA). To support further application of this model in drug development, we conducted a systematic analysis of the estimation performance of the CVS model to infer drug- and system-specific parameters. Specifically, we focused on the impact on model estimation performance when considering differences in available readouts and the impact of study design choices. To this end, a practical identifiability analysis was performed, evaluating model estimation performance for different combinations of hemodynamic endpoints, drug effect sizes, and study design characteristics. The practical identifiability analysis showed that MoA of drug effect could be identified for different drug effect magnitudes and both system- and drug-specific parameters can be estimated precisely with minimal bias. Study designs which exclude measurement of CO or use a reduced measurement duration still allow the identification and quantification of MoA with acceptable performance. In conclusion, the CVS model can be used to support the design and inference of MoA in pre-clinical CVS experiments, with a future potential for applying the uniquely identifiable systems parameters to support inter-species scaling.

Interspecies and in vitro-in vivo scaling for quantitative modeling of whole-body drug pharmacokinetics in patients: Application to the anticancer drug oxaliplatin.

Quantitative systems pharmacology holds the promises of integrating results from laboratory animals or in vitro human systems into the design of human pharmacokinetic/pharmacodynamic (PK/PD) models allowing for precision and personalized medicine. However, reliable and general in vitro-to-in vivo extrapolation and interspecies scaling methods are still lacking. Here, we developed a translational strategy for the anticancer drug oxaliplatin. Using ex vivo PK data in the whole blood of the mouse, rat, and human, a model representing the amount of platinum (Pt) in the plasma and in the red blood cells was designed and could faithfully fit each dataset independently. A "purely physiologically-based (PB)" scaling approach solely based on preclinical data failed to reproduce human observations, which were then included in the calibration. Investigating approaches in which one parameter was set as species-specific, whereas the others were computed by PB scaling laws, we concluded that allowing the Pt binding rate to plasma proteins to be species-specific permitted to closely fit all data, and guaranteed parameter identifiability. Such a strategy presenting the drawback of including all clinical datasets, we further identified a minimal subset of human data ensuring accurate model calibration. Next, a "whole body" model of oxaliplatin human PK was inferred from the ex vivo study. Its three remaining parameters were estimated, using one third of the available patient data. Remarkably, the model achieved a good fit to the training dataset and successfully reproduced the unseen observations. Such validation endorsed the legitimacy of our scaling methodology calling for its testing with other drugs.

Changes in Rosuvastatin Pharmacokinetics During Postnatal Ontogenesis in Rats.

Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in ratsin vivoas a basis for clinical development of formulations for patients < 6 years. Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.

Interspecies Scaling of Human Clearance and Plasma Trough Exposure for Antisense Oligonucleotides: A Retrospective Analysis of GalNAc3-Conjugated and Unconjugated-Antisense Oligonucleotides.

It is well documented and generally accepted that human clearance (CL) of unconjugated single-strand antisense oligonucleotides (ASOs) can be directly predicted from monkeys by body weight (BW) on a mg/kg dose basis. However, the scaling for triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASOs has not been fully established. In this study, we retrospectively analyzed pharmacokinetic data from 9 GalNAc3-conjugated and 12 unconjugated single-stranded ASOs (ten 2'-methoxyethyl and two 2', 4'-constrained ethyl ASOs) to identify an appropriate allometric scaling factor between the two species. In addition, we compared the trough plasma concentrations (Ctrough, a surrogate for tissue exposure) between monkeys and humans at comparable dose levels, aiming at predicting tissue distribution in humans from monkeys. Overall, the median plasma CL ratios (monkey CL/human CL) were 1.05 and 0.94 when CL was normalized by BW, as compared with 0.33 and 0.29 when CL was normalized by body surface area (BSA) for the 12 unconjugated and 9 GalNAc3-conjugated ASOs, respectively. Similarly, the median Ctrough ratios (Ctrough in monkeys/Ctrough in humans) were 0.96 and 1.71, respectively, when Ctrough was normalized by mg/kg dose as compared with 3.10 and 5.50 when Ctrough was normalized by mg/m2 dose for the same unconjugated and conjugated ASOs, respectively. Equivalent CL and dose-normalized plasma Ctrough between monkeys and humans suggest similar pharmacokinetic profiles and tissue distribution between the two species on a per kilogram BW basis. In conclusion, human CL and plasma Ctrough (a surrogate of tissue distribution) can be directly predicted (1:1 or within twofold) from monkeys by BW on a mg/kg dose basis but these parameters can be under- or over-predicted by BSA on a mg/m2 dose basis. These results provide evidence for single species scaling from monkeys to humans directly and, thus, they can facilitate early human dose prediction in ASO drug development.

A mechanism-based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID-19 treatment in humans.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) outbreak initiated the global coronavirus disease 2019 (COVID‐19) pandemic resulting in 42.9 million confirmed infections and > 1.1 million deaths worldwide as of October 26, 2020. Remdesivir is a broad‐spectrum nucleotide prodrug shown to be effective against enzootic coronaviruses. The pharmacokinetics (PKs) of remdesivir in plasma have recently been described. However, the distribution of its active metabolite nucleoside triphosphate (NTP) to the site of pulmonary infection is unknown in humans. Our objective was to use existing in vivo mouse PK data for remdesivir and its metabolites to develop a mechanism‐based model to allometrically scale and simulate the human PK of remdesivir in plasma and NTP in lung homogenate. Remdesivir and GS‐441524 concentrations in plasma and total phosphorylated nucleoside concentrations in lung homogenate from Ces1c −/− mice administered 25 or 50 mg/kg of remdesivir subcutaneously were simultaneously fit to estimate PK parameters. The mouse PK model was allometrically scaled to predict human PK parameters to simulate the clinically recommended 200 mg loading dose followed by 100 mg daily maintenance doses administered as 30‐minute intravenous infusions. Simulations of unbound remdesivir concentrations in human plasma were below 2.48 μM, the 90% maximal inhibitory concentration for SARS‐CoV‐2 inhibition in vitro. Simulations of NTP in the lungs were below high efficacy in vitro thresholds. We have identified a need for alternative dosing strategies to achieve more efficacious concentrations of NTP in human lungs, perhaps by reformulating remdesivir for direct pulmonary delivery.

Interspecies Scaling of Antibody-Drug Conjugates (ADC) for the Prediction of Human Clearance.

Allometric scaling is a useful tool for the extrapolation of pharmacokinetic parameters from animals to humans. The objective of this study was to predict human clearance of antibody–drug conjugates (ADC) allometrically from one to three animal species and compare the predicted human clearance with the observed human clearance. For three animal species allometric scaling, the “Rule of Exponents” (ROE) was used. The results of the study indicated that three-species allometric scaling in association with the ROE provides acceptable prediction (within 0.5–2-fold prediction error) of human clearance. The two-species allometric scaling resulted in substantial prediction error. One-species scaling using a fixed exponent of 1.0 provided acceptable prediction error (within 0.5–2-fold) by monkey, rat, and mouse, in which monkey and rat were comparable. Overall, the predicted human clearance values of ADCs from animal(s) was good. The allometric method proposed in this article can be used to predict human clearance from the animal data and subsequently to select the first-in-human dose of ADCs.

Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments.

Bictegravir (BIC) and tenofovir alafenamide fumarate (TAF), two potent anti-HIV drugs, had been nanoformulated (nBIC-TAF) to achieve once-a-month PrEP coverage. In-vivo mouse experiments for nBIC-TAF exhibited favorable subcutaneous (SC) pharmacokinetics. To probe the clinical suitability of the nBIC-TAF, as the next step, we intend to study nBIC-TAF in non-human primates (NHP), as the best preclinical model to foster clinical trials. Before entering an expensive NHP study, however, we seek to improve our a priori understanding about nBIC-TAF in higher species, having just mouse data. The mechanism-based pharmacokinetic modeling (MBPK) has been used as an appropriate method for pharmacokinetic modeling and interspecies scaling for nanoformulations. Via the use of MBPK, in this work, we created a model for nBIC-TAF able to predict plasma concentration-time curves in NHP. BIKTARVY is a daily oral combination of BIC, TAF, and emtricitabine (Gilead Science, CA), approved for HIV therapy. Using BIKTARVY equivalent dosages (from their NHP studies), we predicted that, following just one SC dose of nBIC-TAF in NHP, both BIC and tenofovir will have detectable and above in vitro efficacy levels for 28 days. Furthermore, the MBPK was able to provide a mechanistic explanation regarding the long-acting mechanism characterizing nBIC-TAF: nanoparticles stores in the SC space from which drugs slowly dissociate. Dissociated drugs in the SC space then buffer the plasma pool over time, yielding an extended-release effect in the plasma. Overall, we predicted for nBIC-TAF a promising long-acting pharmacokinetic in NHP, potentially usable as monthly PrEP. These results will help investigators to gain confidence for facing regulatory submissions at early stages.