Exposure–response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection

To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56).Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies

Performance-Based Quality Specifications: The Link between Product Development and Clinical Outcomes

The design of drug delivery systems and their corresponding dosing guidelines are critical product development functions supported by clinical pharmacokinetic (PK) and pharmacodynamic (PD) data. Largely, the importance of variance and covariance in product and patient attributes is poorly understood. The existence of PK/PD diversity among myriad patient sub-populations further complicates efforts to gauge the importance of product quality variation. Nevertheless, a platform capable of evaluating the effects of product and patient variability on clinical performance was constructed. This dissertation was predicated on requests to re-define pharmaceutical quality in terms of risk by relating clinical attributes to production characteristics. To avoid in vivo studies, simulated experimental trials were conducted using the model drug, theophylline, for which data and models could be acquired from the literature. Where comprehensive data were unavailable (e.g., production variability statistics), initial estimates were acquired via laboratory-scale experiments. Model asthmatic patients were generated using Monte Carlo simulation and published population distributions of various anothropometric measurements, disease rates, and lifestyle factors. Mathematical constructs for in vitro-in vivo correlations provide a linkage between Quality by Design (QbD) product and process models, PK/PD models, and patient population statistics. The combined models formed the foundation for Monte Carlo risk assessments, which characterized the risk of inefficacy and toxicity for dosing of extended-release theophylline tablets. Sensitivity analyses revealed that patient compliance and content uniformity significantly influenced the probability of observing an adverse event. The Monte Carlo risk assessment platform defined the link between the critical quality attributes (CQAs) and clinical performance (i.e., performance-based quality specifications (PBQS)). The PBQS were subsequently utilized to generate process independent design spaces conditioned on inefficacy and toxicity risk. These design spaces, which directly account for the conditional relationships between product quality and patient variability, can be transferred to a specific process via models that relate process critical control parameters to the CQAs. Process Analytical Technology, therefore, can be integrated into the QbD production environment to control the safety and efficacy of the final product. This work demonstrated that process and product knowledge can be used to estimate the risk that final product quality imparts to clinical performance

Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 h of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg of body weight every 12 h versus 24 h) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg, and peripheral volume is 19.6 L/70 kg. For both models, we found that allometric weight scaling, postmenstrual age, creatinine clearance, and daily highest temperature had significant effects on clearance. The presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 mu g/ml for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 h is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the MICs (4 mu g/ml)

Treatment outcomes and medication management of tuberculosis

Tuberculosis (TB) is a bacterial infectious disease. The majority of TB patients in the Netherlands are successfully treated but in some patientsextension of treatment duration is necessary due to complications. Only in a small number of patients this treatment fails. This thesis focuses on the multifaceted medical approach to optimize the treatment of TB and improve treatment outcomes.In the first part of this thesis, we used long-term data from the national tuberculosis registry to determine the risk factors of prolonged and unsuccessful TB treatment in different patients. By identifying risk factors at an early stage, appropriate measures can be taken to reduce their impact and improve TB treatment outcomes. In the second part of this thesis, we evaluated the efficacy of a well-known antibiotic called levofloxacin. We investigated the relationship between the amount of antibiotic in the blood and the effectiveness of the treatment, and side effects by combining and analyzing data from previous studies. We also investigated in patients with a highly resistant form of TB whether they had enough of the antibiotic in their blood to kill the bacteria.Based on this research, we conclude that the amount of antibiotic in the blood differs per patient, and monitoring of this value combined with measuring the sensitivity of the bacteria to the antibiotic is necessary to adjust the dosage and thereby optimize treatment

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Factors Associated with Busulfan Clinical Pharmacology

Busulfan is a bifunctional alkylating agent used in combination with other chemotherapeutics for the ablation of dysfunctional bone marrow prior to haematopoietic stem cell transplantation. Busulfan use is complicated by a large inter-individual and inter-occasion pharmacokinetic variability. Furthermore, the exposure of busulfan (estimated as a cumulative area under the curve) has been associated with dose-limiting toxicities such as sinusoidal obstruction syndrome, which can lead to multi-organ failure and death if left untreated. The research presented in this thesis retrospectively explores SOS incidence in 337 HSCT patients over an eleven-year study period (2006 – 2017) across seven institutions in Australia. Out of 344 busulfan-based conditioning occasions, there were 64 cases of SOS reported. A population pharmacokinetic analysis was developed to explore the pharmacokinetic variability present. Association studies were conducted post hoc and non-parametric and Cox proportional hazards models were developed to better understand the development of SOS post-busulfan use. Lastly, an exploration of the influence of patient genotypes on clinical outcome was conducted. A total of 3241 observations informed the selection of a one-compartment pharmacokinetic model. Inter-occasion and inter-individual variability were characterized for both clearance and volume. Adjusted-ideal bodyweight (kg) and a sigmoidal Emax, maturation function were incorporated as covariates. A post hoc analysis into concomitant medications found a significant decrease in busulfan CL for patients co-administered metronidazole (difference in median CLNORM = 0.05 L/h/kg, n = 17, P < 0.0001), and a marginal increase with dexamethasone (difference in median CLNORM = 0.01 L/h/kg, n = 49, P < 0.01). Overall, cAUC was not significantly associated with SOS, although median Cmax observed on Day 1 of busulfan therapy was higher in patients with SOS (2 μg/mL vs. 2.61 μg/mL, P < 3.7 x 10-5). A multivariate Cox proportional hazard model characterized the hazard of developing SOS as a combination of risk factors: low AIBW, low pre-transplant albumin, younger age and high Cmax. A linear regression analysis on an ADME panel of 67 SNPs in a sub-cohort (223 patients) found found no significant effect of SNPs on busulfan clearance. A logistic regression analysis of the same number of patients over the panel of enzyme-related SNPs failed to report any significant genetic associations with SOS. A separate analysis of 189 patients for polymorphisms of GSTA1 (an enzyme previously associated with busulfan metabolism) showed a 14% – 18% lower clearance (difference in mean CLNORM = 0.03 L/h/kg, P = 0.004 and 0.04 L/h/kg, P = 0.0003) in patients heterozygous and homozygous for the *B allele, respectively. A further categorisation of GSTA1 polymorphisms into activity-based groups was of no additional benefit. In conclusion, the high degree of inter-occasion and inter-individual variability in busulfan pharmacokinetics was reconfirmed through this thesis. Patient specific factors such as GSTA1 polymorphisms affected pharmacokinetic variability, but cAUC was not associated with risk of SOS

Influence of genetic variability on the clinical pharmacology of carbamazepine and lamotrigine

This research programme investigates the influence of genetic variability on the clinical pharmacology of carbamazepine (CBZ) and lamotrigine (LTG). Common polymorphisms in genes that may influence the response to CBZ and LTG include CYP3A4 g.-392A>G, CYP3A5 g.6986A>G, CYP1A2 g.5734C>A, EPHX1 c.337T>C, EPHX1 c.416A>G, UGT2B7 c.802C>T, ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T and SCN2A c.56G>A. The prevalence of these common polymorphisms was evaluated in a 400-strong study population from a single research unit. Minor allele frequency ranged between 3.5% (CYP3A4 -392G) and 48.0% (ABCB1 1236T). Allele and genotype distributions were comparable to published data for other Caucasian populations. The influence of common polymorphisms in drug metabolising enzyme (DME) and sodium channel genes on the optimal dose of CBZ was assessed in a cohort of 70 patients. This study revealed that age and common polymorphisms in the EPHX1 gene (c.337T>C and c.416A>G) are potential predictors for optimal dose of CBZ. The significant effects of EPHX1 variants may be explained by their significant contribution to the inactivation of CBZ. These potential predictors explain approximately 15% of the inter-individual variation in CBZ dose requirements. Preliminary findings suggest that common polymorphisms in DME genes do not form a unique profile which increases the risk of developing intolerable CBZ adverse effects. It is unlikely that common polymorphisms in ABCB1 and SCN2A genes influence the expression and/or activity of their respective proteins to the level at which they can dictate response to LTG therapy. The influence of common polymorphisms in ABCB1 and SCN2A genes on the optimal dose of LTG was assessed in a cohort of 94 patients. Optimal dose in this study was defined as the final dose given to the patients that successfully maintained seizure freedom for at least 1 year with LTG monotherapy. Several basic clinical factors such as age and gender were also examined as potential predictors. The effect of predictors on the optimal dose of LTG was investigated using linear regression analysis. This study revealed that gender and common polymorphisms in the ABCB1 gene (c.1236C>T and c.3435C>T) are potential predictors for optimal dose of LTG. These predictors explain approximately 17% of the inter-individual variation in LTG dose requirement. These findings further highlight the potential role of P-gp in the management of epilepsy. The final study investigated the influence of ABCB1 c.1236C>T and ABCB1 c.3435C>T polymorphisms on the pharmacokinetics of LTG. A total of 156 blood samples from 50 patients receiving LTG monotherapy were available for analysis. The influence of ABCB1 variants was evaluated by population pharmacokinetics. This approach successfully estimated the oral clearance of LTG monotherapy at steady-state. However, the absorption rate constant (Ka) and volume of distribution (Vd) of LTG were poorly estimated. The inclusion of common polymorphisms in the ABCB1 gene in the pharmacokinetic model did not improve the estimation of oral clearance. This may indicate that common variants of ABCB1 do not influence clearance of LTG

A pharmacometric approach to optimal use of second line drugs for multidrug-resistant tuberculosis

Until the recent introduction of short course regimens, treatment regimens for multidrug resistant TB (MDR-TB) were long and toxic. Consequently, only approximately half of MDRTB patients completed their treatment. TB dosing guidelines have historically been unrefined with little consideration for pharmacokinetic/pharmacodynamic relationships. Large knowledge gaps therefore exist in the understanding of pharmacokinetic/pharmacodynamic relationships for both efficacy and toxicity in MDR-TB. My PhD used clinical pharmacology approaches to improve the understanding of drug exposures, toxicity, and exposure-toxicity relationships during the first 12 weeks of MDR-TB therapy. Aims and methods 1. Using non-compartmental analyses, describe the pharmacokinetics of cycloserine and, using regression modelling, explore the association of covariates with cycloserine exposure. 2. Using validated screening tools, describe the incidence of neuropsychiatric toxicity in MDR-TB patients, and explore associations with cycloserine pharmacokinetics. 3. Using a validated pain-rating scale in a crossover study design, investigate whether the addition of a local anaesthetic reduces kanamycin-related injection pain, and explore effects on kanamycin pharmacokinetics. 4. Using geometric mean ratios, compare the exposures of crushed versus whole formulations of pyrazinamide, moxifloxacin, ethionamide, ethambutol, cycloserine, and isoniazid. Results and conclusions We found no measurable terizidone in plasma supporting the hypothesis that terizidone is hydrolysed pre-systemically to cycloserine. The cycloserine time-concentration profile supports once daily dosing of terizidone. We describe a high incidence of peripheral neuropathy in MDR-TB patients with both cycloserine clearance and high-dose pyridoxine significantly associated with neuropathy on multivariate analysis. The addition of a local anaesthetic reduced the pain experienced by MDR-TB patients in the first 15 minutes post intramuscular administration of kanamycin, which could improve adherence to MDR-TB treatment. We also found the bioavailability of crushed isoniazid to be approximately 42% less than the whole tablet formulation, and therefore recommend that the crushing of isoniazid be avoided. Although some recent treatment advances have improved MDR-TB outcomes, enhancing the understanding of drugs used to treat MDR-TB, which continues to have an unacceptably high mortality and treatment-related morbidity, is a public health priority. This thesis comprises four peer-reviewed publications, all of which made a pragmatic contribution to the fight against MDR-TB

Improving antibiotic therapy in critically ill patients through pharmacokinetic dose optimization

Each year, thousands of critically ill patients admitted to Dutch intensive care units suffer from severe bacterial infections. Early and adequate antibiotic treatment significantly lowers the mortality of these infections. The efficacy and safety of antibiotics like gentamicin, vancomycin and ceftazidime depends on the concentrations that are achieved in serum and in infected body tissues. However, it is particularly difficult to achieve adequate antibiotic concentrations in critically ill patients because the pharmacokinetic processes may vary widely, both between these patients and within an individual patient during different stages of the infection. To increase the probability that effective antibiotic concentrations are reached timely in these patients, the use of optimized dosing strategies is recommended. This thesis investigates several of these strategies, ranging from the effect of a higher starting dose for all critically ill patients or for some individuals with specific patient characteristics to the use of continuous infusion or the use of therapeutic drug monitoring