David H. Salinger

Quantitative Prediction of Human Pharmacokinetics for Monoclonal Antibodies

Background and ObjectivesPrediction of human pharmacokinetics for monoclonal antibodies (mAbs) plays an important role for first-in-human (FIH) dose selection. This retrospective analysis compares observed FIH pharmacokinetic data for 16 mAbs to those predicted in humans based on allometric scaling of Cynomolgus monkey pharmacokinetic data.MethodsTen mAbs exhibited linear pharmacokinetics in monkeys based on non-compartmental analysis. For these, simple allometric scaling based on bodyweight was applied to predict human clearance (CL) and volume of distribution (Vd) from those obtained in monkeys. Six mAbs exhibited nonlinear pharmacokinetics in monkeys based on population modelling. For these, a population modelling approach using nonlinear mixed-effects modelling software, NONMEM®, was applied to describe monkey data by a two-compartment pharmacokinetic model with parallel linear and nonlinear elimination from the central compartment. The pharmacokinetic parameters in monkeys were then scaled to humans based on simple allometry. Human concentrationtime profiles of these mAbs were then simulated and compared with those observed in the FIH studies.ResultsAntibodies with linear elimination in monkeys also exhibited linear elimination in humans. For these, observed CL and Vd were predicted within 2.3-fold by allometry. The predictability of human peak serum concentration (Cmax) and area under the serum concentration-time curve (AUC) for mAbs with nonlinear pharmacokinetics in monkeys was, however, concentration dependent. Cmax was consistently overestimated (up to 5.3-fold higher) when below the predicted Michaelis-Menten constant (Km; range 0.3–4 μg/mL). The prediction of human Cmax was within 2.3-fold when concentrations greatly exceeded Km. Similarly, differences between predicted human AUCs and those observed in the FIH studies were much greater at low doses/concentrations. Consequently, predicted drug exposure in humans at low starting doses (range 0.01–0.3 mg/kg) in FIH studies was poorly estimated for three of six mAbs with nonlinear pharmacokinetics.ConclusionsAllometric prediction of human pharmacokinetics may be sufficient for mAbs that exhibit linear pharmacokinetics. For mAbs that exhibited nonlinear pharmacokinetics, the best predictive performance was obtained after doses that achieved target-saturating concentrations.

A dose–response Meta‐Analysis for Quantifying Relative Efficacy of Biologics in Rheumatoid Arthritis

We present a dose–response meta‐analysis to quantify relative efficacy of biologic disease‐modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). There is a strong rationale for this analysis because, although multiple biologics are available, information on head‐to‐head comparisons is limited. Data on the percentage of patients attaining American College of Rheumatology (ACR) 20, 50, and 70 responses were extracted from 50 randomized controlled trials representing 21,500 patients, five mechanisms of action, and nine biologics. The analysis showed that all tumor necrosis factor inhibitors (anti‐TNFs) share the same dose–response relationship for ACR 20, 50, and 70, differing only in potency. Yet there are significant differences in efficacy among the anti‐TNFs due to differences in the clinical dose ranges available. At the suggested starting dose, golimumab was the least efficacious, followed by infliximab, adalimumab, etanercept, and certolizumab. Significant differences in the dose–response relationship were found between anti‐TNFs and other biologics, resulting in differences in efficacy and differential impact of dose titration.

Gene Expression Profiles Normalized in Psoriatic Skin by Treatment with Brodalumab, a Human Anti–IL-17 Receptor Monoclonal Antibody

The IL-17 pathway is an established driver of psoriasis pathogenesis. We examined the detailed molecular and cellular effects of blockade of IL-17 signaling in human psoriatic skin before and following treatment with brodalumab, a competitive inhibitor of the IL-17 Receptor A subunit. Thousands of aberrantly expressed genes in lesional skin normalized within 2 weeks following brodalumab treatment, with conversion of the lesional psoriasis transcriptome to resemble that seen in nonlesional skin. Keratinocyte-expressed genes appeared to normalize rapidly, whereas T cell–specific normalization occurred over six weeks. The three IL-17 ligand genes that are upregulated in lesional skin, IL17A, IL17C, and IL17F, were all downregulated in a dose-dependent manner following brodalumab treatment. Cellular measures also showed a similar pattern with dramatic decreases in keratinocyte hyperplasia within one week, and decreases in infiltrating leukocytes occurred over a longer timescale. Individuals with the highest brodalumab exposure showed normalization of both IL-17–responsive genes and the psoriasis transcriptome, whereas subjects with lower exposures showed transient or incomplete molecular responses. Clinical and molecular response appeared dependent on the extent of brodalumab exposure relative to the expression of IL-17 ligand genes, and reduction of IL-17 signaling into the nonlesional range was strongly correlated with normalization of the psoriasis transcriptome. These data indicate that blockade of IL-17 signaling in psoriatic skin leads to rapid transcriptomal changes initially in keratinocyte-expressed genes, followed by normalization in the leukocyte abnormalities, and demonstrates the essential role of the IL-17R on keratinocytes in driving disease pathogenesis.

A Limited Sampling Schedule to Estimate Individual Pharmacokinetic Parameters of Fludarabine in Hematopoietic Cell Transplant Patients

Purpose: Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS. Experimental Design: A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily i.v. fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve. Results: A two-compartment model best fits the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean squared error for the area under the concentration-time curve for each simulated individual. The LSS times chosen were 0.583, 1.5, 6.5, and 24 hours after the start of the 30-minute fludarabine infusion. Discussion: The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining four blood samples (using the LSS) and maximum a posteriori Bayesian estimation. Conclusion: These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving i.v. fludarabine in the ambulatory clinic. (Clin Cancer Res 2009;15(16):5280–7)

Population pharmacokinetics of brodalumab in healthy adults and adults with psoriasis from single and multiple dose studies.

Brodalumab, a human monoclonal IgG2‐antibody, acts as a potent antagonist at the interleukin‐17 receptor A, which is important in the pathogenesis of psoriasis. To characterize the pharmacokinetics of brodalumab and assess the effects of covariates, brodalumab concentrations from Phase 1a and Phase 2 clinical studies in healthy adults and subjects with psoriasis were used to construct a population PK model. The final two‐compartment model with parallel linear and non‐linear elimination pathways fit the data well. The population typical values for PK parameters CL, V, and Vmax were 0.223 L/day, 4.62 L, and 5.40 mg/day with between‐subject‐variability of 69.2, 69.6, and 25.9%CV, respectively. Body weight (BW) was an important covariate on CL (and Q), V (and V2) and Vmax, with estimated effect exponents of 0.598, 0.849, and 1.12, respectively. Based on simulations from the final model, for doses between 140 and 210 mg, AUC was predicted to be greater than two fold higher in subjects weighing less than 75 kg compared to reference subjects. Age and diagnosis had smaller influence on exposure and was not clinically significant. These data suggest that BW is an important covariate explaining some of the variability in population PK observed in human clinical trials with brodalumab.

Prediction of clinical pharmacokinetics of AMG 181, a human anti‐α4β7 monoclonal antibody for treating inflammatory bowel diseases

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone.

A semi‐mechanistic model to characterize the pharmacokinetics and pharmacodynamics of brodalumab in healthy volunteers and subjects with psoriasis in a first‐in‐human single ascending dose study

Pharmacokinetic‐pharmacodynamic (PK‐PD) modeling can provide a framework for quantitative “learning and confirming” from studies in all phases of drug development. Brodalumab is a human monoclonal antibody (IgG2) targeting the IL‐17 receptor A that blocks signaling by cytokines thought to play a central role in the pathogenesis of psoriasis (IL‐17A, IL‐17F, and IL‐17A/F). We used semi‐mechanistic modeling of single dose, first‐in‐human data to characterize the exposure‐response relationship between brodalumab and the Psoriasis Area and Severity Index (PASI) in a Phase 1 clinical trial. Fifty‐seven healthy volunteers and 25 subjects with moderate to severe psoriasis received single intravenous or subcutaneous administration of placebo or brodalumab (7–700 mg). A two‐compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination pathways described brodalumab PK. The PK‐PASI relationship was characterized by linking a signaling compartment with an indirect response model of psoriatic plaques, where signaling suppressed plaque formation. The concentration of half‐maximal inhibition IC50 was 2.86 µg/mL (SE: 50%). The endogenous psoriatic plaque formation rate of 0.862 (SE: 40%) PASI units/day was comparable with literature precedent. Despite the small sample size and single administration data, this semi‐mechanistic modeling approach provided a quantitative framework to inform design of dose‐ranging Phase 2 studies of brodalumab in psoriasis.

A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.

Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration‐time data following a 2‐hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5‐sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC0‐12h for Q12‐hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC0–8 h for Q8‐hour dosing.

Clinical Trial Simulation to Inform Phase 2: Comparison of Concentrated vs. Distributed First‐in‐Patient Study Designs in Psoriasis

Clinical trial simulation (CTS) and model‐based meta‐analysis (MBMA) can increase our understanding of small, first‐in‐patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose‐ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the psoriasis space, a threshold of greater than a 50 percentage point improvement over placebo effect at the highest feasible drug dose was required for the advancement in psoriasis. Studies testing only placebo and the maximum dose made the correct advancement decision marginally more often than dose‐ranging designs in the majority of the cases. However, dose‐ranging studies in FIP trials offer important design advantages in the form of dose–response (D–R) information to inform Phase 2 dose selection. CTS can increase the efficiency and quality of drug development decision making by studying the limitations and benefits of study designs prospectively.