Ocular Pharmacokinetics of Brimonidine Drug Delivery System in Monkeys and Translational Modeling for Selection of Dose and Frequency in Clinical Trials.

Brimonidine, a selective α 2-adrenoceptor agonist, displays putative retinal cyto- and neuroprotective activity in vitro and in vivo. An intravitreal sustained-release brimonidine implant, Brimonidine Posterior Segment Drug Delivery System (brimonidine DDS), allowing targeted drug delivery to the retina has been developed for potential clinical application. This study evaluates the in vivo posterior segment pharmacokinetics of brimonidine DDS implant in the monkey eye and applies translational pharmacokinetic modeling to predict tissue exposure in the human eye. Anesthetized cynomolgus monkeys received a single intravitreal injection of brimonidine DDS 400 µg implant before removal of study eyes at days 7, 30, 60, 92, 120, and 150 postimplant (three to four animals per time point) for assay of brimonidine in aqueous humor, vitreous, and retina samples. Brimonidine concentrations in the human eye were modeled using a linear, three-compartment model assuming bidirectional distribution to/from the aqueous humor and retina and elimination from the aqueous humor. Monkey tissue volumes were scaled up to human values; intercompartmental and elimination rate constants were assumed to be identical in the two species. Modeling and simulations were performed using NONMEM v. 7.3, R 3.5.1. Brimonidine exposure was highest in the monkey vitreous and retina; concentrations in the central (macula) and peripheral retina were maintained at high levels (>100 ng/g) for 3 to 4 months. Simulated brimonidine concentration-time profiles in human macula indicated that brimonidine DDS 400 µg implant would deliver effective drug concentrations (20.7‒82.2 ng/g, based on animal pharmacology) for approximately 3 months. Accordingly, administration of the 400 µg implant at 3-month intervals is recommended. SIGNIFICANCE STATEMENT: Brimonidine, an α 2-adrenoceptor agonist, is cyto- and neuroprotective in animal models of retinal/optic nerve injury. Brimonidine Posterior Segment Drug Delivery System (brimonidine DDS) is an intravitreal sustained-release implant with potential ophthalmological applications. This study explores the pharmacokinetics of brimonidine DDS 400 µg implant in the monkey eye and uses compartmental modeling to predict human ocular tissue exposure. Targeted retinal brimonidine delivery from vitreous was demonstrated in monkeys. Simulated tissue concentration-time profiles indicated persistence of pharmacologically effective brimonidine concentrations for ≈3 months in human retina.

A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition.

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC50 and in vivo human IC50 values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden. SIGNIFICANCE STATEMENT: Current anti-VEGF treatments for neovascular age-related macular degeneration require frequent (monthly) intravitreal injections and monitoring, which increases patient burden. We developed a mechanistic pharmakinetic/pharmadynamic model to describe the interaction between abicipar (a novel VEGF inhibitor) and VEGF to evaluate the duration of action. The model demonstrates extended abicipar-VEGF target engagement leading to clinical feasibility of up to a 16-week dosing interval. Our model predicted that abicipar 8-week and quarterly dosing schedules maintain virtually complete VEGF inhibition during the 52-week period.

Population pharmacokinetics and pharmacodynamics of IONIS-GCGRRx, an antisense oligonucleotide for type 2 diabetes mellitus: a red blood cell lifespan model.

IONIS-GCGRRx (ISIS 449884) is an antisense oligonucleotide inhibitor of the glucagon receptor (GCGR). The objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-GCGRRx via population-based modeling. The observed data were obtained from a Phase 1 (50, 100, 200, 300 and 400 mg) single- and multiple-dose study in healthy volunteers and a Phase 2 (100 and 200 mg) multiple-dose study in T2DM patients. The PK of IONIS GCGRRx was characterized by two primary systemic compartments and three absorption transit compartments with elimination out of the peripheral compartment. The fasting plasma glucose (FPG) PD was an indirect-response model (inhibition of FPG production) linked to the HbA1c PD model which was a semi-mechanistic model capturing RBC maturation dynamics. Stepwise covariate modeling was performed to identify relevant covariates. In the PK model, bodyweight (BW) was the only significant covariate influencing tissue clearance, tissue volume and plasma volume. Plots of parameter-covariate relations indicate the influence of BW is clinically relevant. In the PD models, baseline HbA1c had a positive correlation with I max and baseline FPG had a negative correlation with the glycosylation rate (k gl ). Simulations from the final model showed that the doses tested in the Phase 2 were at or close to the maximum of the dose-response curve and that dose reduction down to 50 mg resulted in minimal effect to efficacy. The model was useful in supporting the decision for dose reduction in a subsequent trial.

A model-based approach to predicting the human pharmacokinetics of a monoclonal antibody exhibiting target-mediated drug disposition.

In the drug discovery and development setting, the ability to accurately predict the human pharmacokinetics (PK) of a candidate compound from preclinical data is critical for informing the effective design of the first-in-human trial. PK prediction is especially challenging for monoclonal antibodies exhibiting nonlinear PK attributed to target-mediated drug disposition (TMDD). Here, we present a model-based method for predicting the PK of PF-03446962, an IgG2 antibody directed against human ALK1 (activin receptor-like kinase 1) receptor. Systems parameters as determined experimentally or obtained from the literature, such as binding affinity (k(on) and k(off)), internalization of the drug-target complex (k(int)), target degradation rate (k(deg)), and target abundance (R(0)), were directly integrated into the modeling and prediction. NONMEM 7 was used to model monkey PK data and simulate human PK profiles based on the construct of a TMDD model using a population-based approach. As validated by actual patient data from a phase I study, the human PK of PF-03446962 were predicted within 1- to 2-fold of observations. Whereas traditional approaches fail, this approach successfully predicted the human PK of a monoclonal antibody exhibiting nonlinearity because of TMDD.

Effect of Anti-VEGF Therapy on the Disease Progression of Neovascular Age-Related Macular Degeneration: A Systematic Review and Model-Based Meta-Analysis.

Anti-vascular endothelial growth factor (VEGF) therapy is used to slow the disease progression of neovascular age-related macular degeneration. Due to the treatment burden of frequent intravitreal injections, anti-VEGFs are often used on treat and extend protocols rather than the labeled frequency. The current goal of anti-VEGF drug development is to minimize treatment burden by reducing the number of intravitreal injections. The purpose of this systemic review and model-based meta-analysis (MBMA) was to (1) perform modeling to describe the disease progression of neovascular age-related macular degeneration in the absence of treatment, as well as in the presence of abicipar, aflibercept, brolucizumab, or ranibizumab intervention; (2) and to simulate virtual head-to-head comparisons among the drugs with an extended dose schedule of once every 12 weeks (Q12). Data sources were PubMed, internal Allergan data, www.clinicaltrials.gov, and www.clinicaltrialsregister.eu. Eligibility assessment was performed by 2 independent review authors. Randomized, controlled trials that had at least 1 arm with an anti-VEGF (aflibercept, abicipar, bevacizumab, brolucizumab, pegaptanib, or ranibizumab), a control arm of placebo or anti-VEGF, a treatment duration of at least 4 months, reported best-corrected visual acuity data, and at least 20 patients were included. A total of 22 trials, consisting of 55 arms, from across 9500+ subjects and 500+ best-corrected visual acuity observations were used to develop the model. Consistent with reported data, results from the model showed that abicipar Q12 underperformed ranibizumab (every 4 weeks), aflibercept (every 4 weeks), and brolucizumab (every 8 weeks/Q12) labeled dosing schedules. However, when all drugs were virtually tested using the extended schedule, abicipar outperformed ranibizumab and aflibercept and produced a similar week 52 change from baseline as brolucizumab. Predicted week 52 changes from baseline were 5.92 ± 1.02, 3.04 ± 1.61, 6.61 ± 0.284, and 3.02 ± 2.35 best-corrected visual acuity letters for abicipar, aflibercept, brolucizumab, and ranibizumab, respectively, using the Q12 schedule. Results demonstrate the feasibility of Q12 dosing with clinically meaningful letter gains for abicipar and brolucizumab. The model developed under this MBMA has utility for exploring different regimens for existing or novel anti-VEGF agents.

Pharmacokinetic-pharmacodynamic and response sensitization modeling of the intraocular pressure-lowering effect of the EP4 Agonist 5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate (PF-04475270).

Developing a population-based pharmacokinetic-pharmacodynamic (PKPD) model is a challenge in ophthalmology due to the difficulty of obtaining adequate pharmacokinetic (PK) samples from ocular tissues to inform the pharmacodynamic (PD) model. Using limited PK data, we developed a preclinical population-based PD model suitable for capturing the time course of dog intraocular pressure (IOP) that exhibited time-dependent sensitization after topical administration of PF-04475270 [5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate]. A physiologically relevant PK model was chosen to simultaneously capture the concentration profiles of CP-734432, a potent EP4 agonist and the active metabolite of PF-04475270, sampled from three ocular tissues of the anterior chamber: cornea, aqueous humor, and iris-ciliary body. Two population-based PD models were developed to characterize the IOP lowering profiles: model I, a standard indirect-response model (IRM); and model II, an extension of a standard IRM that empirically incorporated a response-driven positive feedback loop to account for the observed PD sensitization. The PK model reasonably described the PK profiles in all three ocular tissues. As for the PD, model I failed to capture the overall trend in the population IOP data, and model II more adequately characterized the overall data set. This integrated PKPD model may have general utility when PD sensitization is observed and is not a result of time-dependent PK. In addition, the model is applicable in the ophthalmology drug development setting in which PK information is limited but a population-based PD model could reasonably be established.

Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.

Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Qp = 0.572 L/h, QCSF = 0.069 L/h, CLp = 2.50 L/h, CLCSF = 0.133 L/hr, VCSF = 0.441 L, Vp = 32.0 L, Vsystemic_tissue = 429 L, and VCNS_tissue = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on VCSF , Vp , and CLp . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.

A method for optimizing dosage regimens in oncology by visualizing the safety and efficacy response surface: analysis of inotuzumab ozogamicin.

PURPOSE: The aim of this investigation was to develop a quantitative method to optimize inotuzumab ozogamicin (InO) dosage regimen in patients with indolent non-Hodgkin lymphoma (NHL) by simultaneously balancing safety and efficacy. METHODS: Pharmacokinetics (PK), safety and efficacy data were obtained from a phase 2 trial of InO administered intravenously to patients (n = 81) with indolent NHL. The PK was described by a two-compartment model which was linked to: (1) an exponential tumor growth model to describe tumor size time course (efficacy determinant expressed as objective response rate) and (2) a precursor-dependent platelet inhibition model to describe platelet time course (safety determinant expressed as thrombocytopenia grade). The model was used to simulate virtual trials to construct safety and efficacy response surfaces. Using the simulated safety and efficacy contours, a clinical utility index (CUI) contour was then constructed, from which optimal InO regimens were then selected. RESULTS: The model-simulated efficacy response surface indicated near-optimal efficacy of InO at the dosage regimen used in the trial (1.8 mg/m(2) every 4 weeks). The model-simulated safety response surface indicated that modifying the dosage regimen resulted in modest improvements in safety with little compromise in efficacy. The CUI contour identified 2 mg/m(2) every 10, 11, or 12 weeks as the "sweet spot" for optimal InO dosage regimen in patients with indolent NHL. CONCLUSION: An approach to dosage regimen optimization was developed for simultaneously balancing safety and efficacy. This approach allows objective identification of optimal dosage regimens from early trial information and thus has broad utility across oncology trials.

Modeling, simulation, and translation framework for the preclinical development of monoclonal antibodies.

The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic-pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.

Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab.

PURPOSE: Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20(+)/CD22(+) B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. RESULTS: In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m(2)) was confirmed to be the same as that for single-agent INO (1.8 mg/m(2)). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. CONCLUSION: R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20(+)/CD22(+) B-cell NHL.

P-glycoprotein induction and tumor cell-kill dynamics in response to differential doxorubicin dosing strategies: a theoretical pharmacodynamic model.

PURPOSE: The objectives of this work were 1) to develop a theoretical pharmacodynamic model that captures dynamic changes resulting from drug/therapy mediated P-glycoprotein (P-gp) induction and 2) to compare the pharmacodynamic outcomes of several doxorubicin (DOX) dosing schemes through simulations. METHODS: We developed a theoretical model that included a pharmacokinetic (PK) model for intracellular DOX-mediated P-gp induction and a pharmacodynamic (PD) model using a threshold trigger function for tumor cell-kill. In this model, both the level of P-gp induction and rate of tumor cell death were modulated by intracellular DOX concentration. Most model parameters were obtained from literature sources, and a few were either fixed or reasonably estimated. RESULTS: Comparative dosing simulations showed that a 10-week constant infusion in which a tumor cell population was continuously exposed to the drug did not produce the best PD profile. On the other hand, dosing schemes where the cell population was initially challenged with a high dose, followed by intermittent dosing, generated the best PD profile. The favorable outcome of the latter dosing schemes was correlated with the lowest expression of P-gp in terms of area under the curve (AUC) during treatment period. CONCLUSIONS: The simulations led us to conclude that drug resistance, particularly resistance caused by P-gp overexpression, induced during chemotherapy may, in part, be circumvented by designing optimal dosing strategies that minimize P-gp induction.