A population pharmacokinetic and pharmacokinetic-pharmacodynamic analysis of vupanorsen from phase I and phase II studies.

Vupanorsen (PF-07285557) is a second-generation ligand-conjugated 2'O-methoxyethyl modified antisense oligonucleotide designed to target angiopoietin-like 3 (ANGPTL3) mRNA expressed by the liver, shown to reduce lipids and apolipoproteins in subjects with dyslipidemia. Using pooled data from two phase I studies of participants with elevated triglycerides (Western: n = 48 and Japanese: n = 12), and two phase II studies of patients with hypertriglyceridemia, diabetes, and nonalcoholic fatty liver disease (n = 105), and statin-treated patients with dyslipidemia (n = 286), we developed population pharmacokinetic (PK) and PK/pharmacodynamic (PK/PD) models. Efficacy target values were set a priori to -75%, -60%, and -35% for ANGPTL3, triglyceride (TG), and non-high-density lipoprotein-cholesterol (non-HDL-C), respectively. Covariates evaluated via a full model approach included baseline body weight, age, estimated glomerular filtration rate (eGFR), anti-drug antibody (ADA) status, sex, and race. Vupanorsen population PK was well-characterized by a two-compartment model with first-order absorption and elimination. Apparent clearance (CL/F) for ADA-positive, female, and Asian participants was estimated to be about 62% (relative standard error 12%), 18% (9%), and 30% (20%) lower than ADA-negative, male, and non-Asian participants, respectively. The associations between CL/F and Black race, age, and eGFR were negligible. The developed population PK/PD model was robust to predict the dose-response relationships. The model predicted that ANGPTL3 target reduction of 75% can be sufficiently achieved with a 320-mg monthly dose of vupanorsen, but target values for TG and non-HDL-C were not expected to be achieved at doses up to 320 mg monthly in patients with dyslipidemia.

Comparison of Patterns of Non-suicidal Self-Injury and Emotion Dysregulation Across Mood Disorder Subtypes.

Introduction: Non-suicidal self-injury (NSSI) is frequently encountered in patients with mood disorders. Emotion dysregulation (ED), frequently observed in mood disorders, could be a major mediating factor in NSSI. The aim of this study was to explore differences in NSSI behavior and ED across mood disorder subtypes. The relationships between childhood trauma and NSSI and ED were also explored. Methods: A total of 191 patients with mood disorders were included in this study. The patterns of NSSI behavior and ED across patients with bipolar I disorder (BD-I), bipolar II disorder (BD-II), and major depressive disorder (MDD) were compared. Results: More than half (54%) of the subjects experienced NSSI. Patients with BD-II and MDD engaged in NSSI behavior more frequently than those diagnosed with BD-I. NSSI behaviors in patients with BD-II most commonly included cutting, whereas hitting behaviors were most common among other groups. Patients with BD-II and MDD reported more severe ED than those with BD-I. In the case of childhood trauma, those with BD-II and MDD reported greater emotional neglect than those with BD-I. Structural equation modeling revealed that ED mediated the association between childhood trauma and NSSI. Conclusion: BD-I was associated with less frequent NSSI behavior and less severe ED than BD-II and MDD. ED mediated the association between childhood trauma and NSSI. Promoting emotion regulation strategies could prevent NSSI behavior in patients with mood disorders.

Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-ß Peptides in Randomized Phase I Studies.

γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-ß (Aß) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aß species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse eventswere deemed not drug related. PF-06648671 decreased Aß42 and Aß40 concentrations in CSF, with greater effects on Aß42, and increased Aß37 and Aß38 levels, particularly Aß37. No significant change in total Aß was observed. The PK/PD model well described the tendency of observed CSF Aß data and the steady-state effects of PF-06648671, supporting its use for predicting central Aß effects and optimal dose selection for GSMs in future trials.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.

PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-ß (Aß) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aß peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aß1-40 and Aß1-42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development.

Iron supplements in nursing home patients associated with reduced carbamazepine absorption.

Persons in nursing homes receive a number of medications that may interfere with the pharmacokinetics of carbamazepine (CBZ). The aim of our study was to determine factors that may affect the pharmacokinetics of CBZ in elderly nursing home patients. METHODS: CBZ concentration data collected from 60 nursing homes across the US were evaluated. Inclusion criteria included residency in a nursing home for at least 2 months, age 65 years or older, a stable dosing regimen of CBZ for at least 4 weeks (considered steady state), available CBZ concentration, and complete information regarding all co-medications. Using a nonlinear mixed-effects model, the data were adequately described by a one-compartment model with first-order absorption and elimination. Goodness-of-fit plots, plausibility of parameter estimates, visual predictive check and nonparametric bootstrap were used to evaluate the models. MAIN FINDINGS: The final data set consisted of 345 CBZ concentrations from 99 subjects (38 males, 61 females). The population estimate of apparent clearance (CL/F) for a 70-kg person was 3.69 L/hr (RSE 6.9%). Residents were receiving either immediate (93.9%) or extended release (6.1%) formulation of CBZ and the Ka of each formulation was fixed to literature values. Age, sex, and co-medications had no effect on CL/F and apparent volume of distribution. Iron supplementation, which was taken by 16% of the residents, resulted in a 33% decrease in bioavailability (p < 0.001). No other medications were found to have an effect. CONCLUSIONS: Results from this pharmacokinetic study indicate that use of iron supplementation is associated with a reduction in absorption of CBZ and may need to be considered when dosing CBZ in patients taking iron supplementation.

Modeling of the parathyroid hormone response after calcium intake in healthy subjects.

Plasma ionized calcium (Ca(2+)) concentrations are tightly regulated in the body and maintained within a narrow range; thus it is challenging to quantify calcium absorption under normal physiologic conditions. This study aimed to develop a mechanistic model for the parathyroid hormone (PTH) response after calcium intake and indirectly compare the difference in oral calcium absorption from PTH responses. PTH and Ca(2+) concentrations were collected from 24 subjects from a clinical trial performed to evaluate the safety and calcium absorption of Geumjin Thermal Water in comparison with calcium carbonate tablets in healthy subjects. Indirect response models (NONMEM Ver. 7.2.0) were fitted to observed Ca(2+) and PTH data, respectively, in a manner that absorbed but unobserved Ca(2+) inhibits the secretion of PTH. Without notable changes in Ca(2+) levels, PTH responses were modeled and used as a marker for the extent of calcium absorption.

Modeling longitudinal daily seizure frequency data from pregabalin add-on treatment.

The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add-on therapy. Models were developed in a stepwise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (relative standard error [RSE] 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra-Poisson variation, was estimated to be 0.330 (RSE 11.7%). Interindividual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate constant of 0.272 year⁻¹ (RSE 26.8%). A mixture model was applied to classify responders/nonresponders to pregabalin treatment. Within the responders, λ decreased exponentially with respect to dose with a constant of 0.00108 mg⁻¹ (RSE 11.9%). The estimated responder rate was 66% (RSE 27.6%). Simulation-based diagnostics showed the model reasonably reproduced the characteristics of observed data. Highly variable daily seizure frequency was successfully characterized incorporating baseline characteristics, time effect, and the effect of pregabalin with classification of responders/nonresponders, all of which are necessary to adequately assess the efficacy of antiepileptic drugs.

Longitudinal aggregate data model-based meta-analysis with NONMEM: approaches to handling within treatment arm correlation.

Literature data are often reported as multiple (longitudinal) mean outcomes observed in several groups of patients within a study. Observations within a study are correlated because the patients come from a common population, and the mean observations over time within a treatment arm are correlated because they are based on the same set of patients. As a result, model-based meta-analysis may require more than two levels of random effects to correctly characterize this correlation structure. Using simulation, we explored and evaluated ways to implement multi-level random effects in NONMEM. Simulation models that were linear and non-linear in the random effects were investigated. We compared estimation models that included study and/or treatment arm-level random effects, with and without residual correlation. With all estimation strategies, the fixed random effects parameters were accurately estimated. With regard to correctly characterizing the variability, models that accounted for correlation within a study and treatment arm over time were the best in some situations, while models that accounted for study-level correlation only were better in others. Models that included only treatment arm-level random effects were not superior in any scenario.

Likelihood based approaches to handling data below the quantification limit using NONMEM VI.

PURPOSE: To evaluate the likelihood-based methods for handling data below the quantification limit (BQL) using new features in NONMEM VI. METHODS: A two-compartment pharmacokinetic model with first-order absorption was chosen for investigation. Methods evaluated were: discarding BQL observations (M1), discarding BQL observations but adjusting the likelihood for the remaining data (M2), maximizing the likelihood for the data above the limit of quantification (LOQ) and treating BQL data as censored (M3), and like M3 but conditioning on the observation being greater than zero (M4). These four methods were compared using data simulated with a proportional error model. M2, M3, and M4 were also compared using data simulated from a positively truncated normal distribution. Successful terminations and bias and precision of parameter estimates were assessed. RESULTS: For the data simulated with a proportional error model, the overall performance was best for M3 followed by M2 and M1. M3 and M4 resulted in similar estimates in analyses without log transformation. For data simulated with the truncated normal distribution, M4 performed better than M3. CONCLUSIONS: Analyses that maximized the likelihood of the data above the LOQ and treated BQL data as censored provided the most accurate and precise parameter estimates.

Population pharmacokinetics of valproic acid concentrations in elderly nursing home residents.

The objective of this study was to identify factors that affect valproic acid (VPA) apparent clearance (CL/F) in elderly nursing home residents. Inclusion criteria included residency in a nursing home for at least 2 months, aged 65 years or older, a stable dosing regimen of VPA for at least 4 weeks, VPA concentration, and complete dosing information. CL/F was analyzed by a nonlinear mixed effects model. A one-compartment model with first-order absorption and elimination was used. Both volume and absorption rate constant were fixed (14 L and 1 hr, respectively). Covariates were tested by forward inclusion and backward elimination. Interindividual variability in clearance was estimated using an exponential error model and expressed as a coefficient of variation. Residual error was estimated using a combined additive and constant coefficient of variation error model. The study consisted of 405 observations from 146 (52 men, 94 women) elderly nursing home residents. CL/F was not affected by age or weight. The population CL/F was 0.843 L/hr. CL/F was 1) 27% lower in female residents; 2) 41% greater when the resident was on concomitant metabolic inducers carbamazepine or phenytoin cotherapy; and 3) 25% greater when the syrup formulation was used. Variability in CL/F was 32.9%. Coefficient of variation and standard deviation of the residual error were 18.2% and 10.6 mg/L, respectively. The increased CL/F in patients taking VPA syrup may be the result of a decreased bioavailability (F) rather than an increased CL that could be associated with pathology requiring use of the syrup rather than an inherent property of the drug formulation. The results from this study may be useful for individualizing dose regimens in the nursing home population based on patient-specific factors.

Inherent correlation between dose and clearance in therapeutic drug monitoring settings: possible misinterpretation in population pharmacokinetic analyses.

During the course of therapeutic drug monitoring (TDM), doses are adjusted to attain a target concentration range and a correlation between clearance (CL) and dose is introduced. In population pharmacokinetic analyses of such TDM data, CL has frequently been modeled as a function of dose. This paper demonstrates by simulation methodology that the TDM process does indeed introduce a correlation between dose and CL which can be interpreted as a nonlinearity. Using literature values of carbamazepine pharmacokinetics, three steady-state concentrations were simulated following a standard 1000 mg total daily dose (TDD) regimen in 100 in silico subjects. A set of clinical rules was established to adjust the TDD based on these three concentrations, as might be done in the clinical setting. Another set of concentrations using these TDM-derived TDDs for each subject (600-1600 mg) was simulated. A standard population pharmacokinetic analysis of the post-TDM data was conducted using NONMEM. This process was replicated 100 times to estimate the type II error rate. When CL was modeled without TDD, plots of WRES versus PRED demonstrated a clear pattern, as did the delta plots of CL (CL minus TVCL) versus TDD, suggesting the covariate TDD should be incorporated into the model. After TDD was included in the model for CL, the objective function value decreased by an average of 75.7 (p < 0.001). In addition, the inter-individual variability in CL expressed as a coefficient of variation decreased by an average of 9.9% and the diagnostic plots improved. Although CL was simulated to be independent of TDD, it was identified as an important covariate using standard approaches in a simulated TDM setting in 100% of the replicated simulation studies. The TDM process introduces a correlation between CL and TDD that can be misinterpreted as nonlinearity in the system.