Model-informed drug repurposing: A pharmacometric approach to novel pathogen preparedness, response and retrospection.

During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based meta-analysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). RESULTS: A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. CONCLUSIONS: PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.

Model-Based Meta-Analysis Supporting the Combination of Acetaminophen and Topical Diclofenac in Acute Pain: A Therapy for Mild-to-Moderate Osteoarthritis Pain?

INTRODUCTION: Acetaminophen and topical diclofenac (AtopD) have complementary mechanisms of action and are therefore candidates for combination use in osteoarthritis (OA) pain. However, an evidence gap exists on their combination use in OA pain. This study aimed to assess the effects of this combination and compare its performance relative to monotherapies on pain score reduction and opioid-sparing effect by leveraging evidence from acute pain setting using a model-based meta-analysis (MBMA). METHODS: A literature search was conducted using the MEDLINE database to identify randomized controlled trials (RCTs) studying the combination for acute pain. Subsequently, an MBMA of RCTs was implemented in conjunction with extrapolation principles to infer efficacy in the population of interest. Pain score reduction and opioid-sparing effect (OSE) were selected as the measures of efficacy. RESULTS: A total of 11 RCTs encompassing 1396 patients were included. Exploratory evaluation revealed AtopD combination to show greater pain score reduction versus acetaminophen monotherapy. However, pain score reduction was more susceptible to confounding by opioid patient-controlled analgesia (PCA) than OSE. Therefore, a parsimonious MBMA evaluating OSE was developed from 5 of the 11 RCTs (n = 353 patients). The analysis revealed a statistically significant interaction coefficient, suggesting a reduction of 32% in opioid use with the combination versus acetaminophen monotherapy. Differences in the effect size of the combination were less conclusive versus diclofenac monotherapy. CONCLUSION: Our results indicate greater pain reduction and opioid-sparing efficacy for the AtopD combination versus acetaminophen monotherapy. Given the similar pain pathways and mechanisms of action of the two drugs in acute and mild-to-moderate OA pain, comparable beneficial effects from the combination therapy may be anticipated following extrapolation to chronic OA pain. Prospective RCTs and real-world studies in OA pain are needed to confirm the differences in the efficacy of the combination treatment observed in our study.

Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain.

INTRODUCTION: The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). METHODS: A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0-1 × ULN, > 1.5-2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. RESULTS: A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26 weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500-4000 mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74-29.20), 1.35% (95% CI: 0.17-2.51) and 0.01% (95% CI: 0.00-0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. CONCLUSIONS: Overall, our analysis shows that short-term (~ 8-16 weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.

Predicted heart rate effect of inhaled PF-00610355, a long acting ß-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease.

AIM: To assess the cardiovascular effects of a new inhaled long-acting ß-adrenoceptor agonist PF-00610355 in COPD patients. METHODS: Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non-linear mixed-effects models. The median heart rate increase in COPD patients for doses of PF-00610355 up to 280 µg once daily was simulated with the final pharmacokinetic/pharmacodynamic (PKPD) model. RESULTS: An Emax model accounting for delayed on-and off-set of the PF-00610355-induced change in heart rate was developed. The predicted potency in COPD patients was three-fold lower compared with healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo-corrected increase of 2.7 (0.90-4.82) beats min(-1) in COPD patients for a PF-00610355 dose of 280 µg once daily, with 19% subjects experiencing a heart rate increase of more than 20 beats min(-1) compared with 8% in the placebo group. CONCLUSIONS: This PKPD analysis supports the clinical observation that no relevant effects of PF-00610355 on heart rate in COPD patients should be expected for doses up to 280 µg once daily.

Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations.

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: -0.03%[-0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[-1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment.

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age.

PURPOSE: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation bridging. METHODS: Several models were developed in pediatric and adult populations to relate steady-state trough plasma concentrations (C(min)) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. KEY FINDINGS: A two-compartmental population PK model with first-order absorption described the time course of topiramate C(min) as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK-PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C(min) and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK-PD modeling data, the dosing regimen expected to achieve a 65-75% seizure freedom rate after 1 year for pediatric patients age 2-10 years is approximately 6-9 mg/kg per day. SIGNIFICANCE: This analysis indicated no difference in PK-PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2-10 years of age.

Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose selection in patients with rheumatoid arthritis (RA).

R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

BACKGROUND AND OBJECTIVES: Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. METHODS: Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. RESULTS: Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. CONCLUSION: Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

Characterizing systemic exposure of inhaled drugs: application to the long-acting ß2-agonist PF-00610355.

BACKGROUND AND OBJECTIVES: PF-00610355 is an orally inhaled long-acting ß2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects. This analysis characterizes PF-00610355 using an integrated analysis of systemic exposure, across trials and patient populations. METHODS: A total of 6,107 samples of PF-00610355 plasma concentration, collected in 264 subjects from eight studies in healthy volunteers, asthma, and COPD patients, were analyzed using non-linear mixed-effects models. Model-based mean (95 % CI) exposure profiles for a range of PF-00610355 doses in COPD patients were simulated. RESULTS: PF-00610355 exposure profiles were described by a three-compartment disposition model with first-order absorption through a transit compartment. Patient status, inhalation device, and demographic factors were found to influence systemic drug exposure. Relative fine particle dose had a minor effect, whereas no effect of baseline lung function on the systemic exposure was found. An implicit method to address pharmacokinetic variability between occasions of drug intake yielded similar results as the established explicit method, yet in a much more efficient way. CONCLUSION: The estimated systemic pre-dose and maximum PF-00610355 plasma concentration was 23 and 38 % in COPD patients compared to healthy volunteers, respectively. The analysis illustrated the value of an integrated pharmacokinetic analysis to address specific challenges in the clinical development of long-/ultra-long-acting ß2-agonists and inhaled compounds in general, both in relation to selecting a safe starting dose in patients, but also in understanding exposure and systemic safety information across different patient populations and different inhalation devices/formulations.

JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity.

PURPOSE: Histone deacetylase (HDAC) inhibitors have shown promising clinical activity in the treatment of hematologic malignancies, but their activity in solid tumor indications has been limited. Most HDAC inhibitors in clinical development only transiently induce histone acetylation in tumor tissue. Here, we sought to identify a "second-generation" class I HDAC inhibitor with prolonged pharmacodynamic response in vivo, to assess whether this results in superior antitumoral efficacy. EXPERIMENTAL DESIGN: To identify novel HDAC inhibitors with superior pharmacodynamic properties, we developed a preclinical in vivo tumor model, in which tumor cells have been engineered to express fluorescent protein dependent on HDAC1 inhibition, thereby allowing noninvasive real-time evaluation of the tumor response to HDAC inhibitors. RESULTS: In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ-26481585. Once daily oral administration of JNJ-26481585 induced continuous histone H3 acetylation. The prolonged pharmacodynamic response translated into complete tumor growth inhibition in Ras mutant HCT116 colon carcinoma xenografts, whereas 5-fluorouracil was less active. JNJ-26481585 also fully inhibited the growth of C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin showed modest activity. Further characterization revealed that JNJ-26481585 is a pan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L). CONCLUSIONS: The potent antitumor activity as a single agent in preclinical models combined with its favorable pharmacodynamic profile makes JNJ-26481585 a promising "second-generation" HDAC inhibitor. The compound is currently in clinical studies, to evaluate its potential applicability in a broad spectrum of both solid and hematologic malignancies.

Modeling and simulation of sexual activity daily diary data of patients with female sexual arousal disorder treated with sildenafil citrate (Viagra).

PURPOSE: To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies. MATERIALS: Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. Simulations were performed to evaluate the expected clinical response in patients with FSAD. RESULTS: The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women. CONCLUSION: A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.