Pharmacokinetics and Pharmacodynamics of Etripamil, an Intranasally Administered, Fast-Acting, Nondihydropyridine Calcium Channel Blocker.

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60 mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers.

Population pharmacokinetic and pharmacodynamic modeling of acetazolamide in peritoneal dialysis patients and healthy volunteers.

PURPOSE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). METHODS: Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. RESULTS: As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg. CONCLUSION: Both PK and PD are significantly altered in dialysis patients.

Performance of different population pharmacokinetic algorithms.

BACKGROUND: There has been an increased focus on population pharmacokinetics (PK) to improve the drug development process since the "Critical Path paper" by the Food and Drug Administration. This increased interest has given rise to additional algorithms. OBJECTIVES: The purpose of this exercise was to compare the new algorithms iterative-2-stage (ITS) and maximum likelihood expectation maximization (MLEM) available in ADAPT 5 with other methods. METHODS: A total of 29 clinical trials with different study designs were simulated. Different algorithms were used to fit the simulated data, and the estimated parameters were compared with the true values. The algorithms ITS and MLEM were compared with the standard-2-stage, Iterative-2-Stage (IT2S) method in the IT2S package and the first-order conditional estimate (FOCE) method in NONMEM version VI. Imprecision and bias for the population PK parameters, variances, and individual PK parameters were used to compare the methods. RESULTS: Population PK parameters were well estimated and bias low for all nonlinear mixed effect modeling approaches. These approaches were superior to the standard-2-stage analyses. The algorithm MLEM was better than IT2S and ITS in predicting the PK and variability parameters. Residual variability was better estimated using MLEM and FOCE. A difference in the estimation of the variance exists between FOCE and the other methods. Variances estimated with FOCE often had shrinkage issues, whereas MLEM in ADAPT 5 had practically no shrinkage problems. Using MLEM, a reduction from 3000 to 1000 samples in the expectation maximization step had no impact on the results. CONCLUSIONS: The new algorithm MLEM in ADAPT 5 was consistently better than IT2S and ITS in its prediction of PK parameters, variances, and the residual variability. It was comparable with the FOCE method with significantly fewer shrinkage issues in the estimation of variance. The number of samples used in the expectation maximization step with MLEM did not influence the results.

Pharmacokinetics and Pharmacodynamics of a Proposed Pegfilgrastim Biosimilar MSB11455 Versus the Reference Pegfilgrastim Neulasta in Healthy Subjects: A Randomized, Double-blind Trial.

PURPOSE: MSB11455 is a proposed biosimilar to the reference pegfilgrastim (Neulasta®). This pivotal equivalence study (NCT03251248) assessed the pharmacokinetic and pharmacodynamic equivalence of MSB11455 to the reference product. METHODS: This 2-way, 2-sequence, group-sequential, crossover study was conducted in healthy subjects. Subjects received a single subcutaneous dose of MSB11455 or the reference product (both 6 mg/0.6 mL) on Day 1 of each study period. Pharmacokinetic and pharmacodynamic (absolute neutrophil count; ANC) samples were taken predose and up to day 16 post-dose. Non-compartmental parameters were calculated. Immunogenicity samples were taken pre-dose and up to day 84 after the first dose. Safety was assessed throughout the study. FINDINGS: A total of 292 subjects were randomized to therapy and treated; 244 received both treatments. For all primary pharmacokinetic and pharmacodynamic parameters, 90% repeated confidence intervals of geometric means ratio of MSB11455 to the reference product were within the pre-defined equivalence range (80.00%-125.00%) for AUC0-∞ (96.59-112.82); AUC0-last (97.29-113.96), Cmax (97.13-114.99), maximum observed effect on ANC (98.74-102.39), and area under the effect-time curve from time zero to time to last quantifiable concentration (97.30-100.23). Safety, tolerability, and immunogenicity were comparable between treatments. No filgrastim-specific neutralizing antibodies were detected with either treatment sequence. IMPLICATIONS: Pharmacokinetic and pharmacodynamic equivalence of MSB11455 and the reference product was shown, with comparable immunogenicity, safety, and tolerability between treatments. The study supports the biosimilarity of MSB11455 to the reference product. ClinicalTrials.gov identifier: NCT03251248.

Population pharmacokinetic and pharmacodynamic analysis of pegloticase in subjects with hyperuricemia and treatment-failure gout.

Pegloticase is designed to convert urate into the easily excretable allantoin to treat hyperuricemia in gout. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4- and 8-mg doses or every 4 weeks at 8- or 12-mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and covariates were investigated (age, gender, race, body weight, ideal body weight, and antibody response). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1-compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (E(max)) function. Pegloticase suppressed uric acid levels up to 83%. Weight only affected clearance and volume of distribution. No covariates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2-hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.

A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism.

Thyroxine hormone has been recognised since the early part of the nineteenth century and levothyroxine has been available since the mid-nineteenth century as a replacement for deficient thyroid hormones. While levothyroxine remains the staple treatment for hypothyroidism even to this day, its optimal use can be challenging. As is often the case with older drugs, the pharmacokinetics of levothyroxine is often under-appreciated or misunderstood and many factors influence the optimal dosing of levothyroxine. This article will review the pharmacokinetics of levothyroxine in the treatment of hypothyroidism and highlight major concepts that should aid both clinicians and researchers.

Aluminum toxicokinetics in peritoneal dialysis patients.

CONTEXT: Despite the risk of aluminum (Al) toxicity in dialysis patients, little is known about its toxicokinetics (TK) in this population. A national contamination of dialysate solutions with Al provided the opportunity to study Al TK in peritoneal dialysis (PD) patients and to better understand the influence of covariates on its disposition. METHODS: Al levels in serum and dialysate as well as other laboratory values were collected prospectively from 83 PD patients after correction of Al contamination. Population TK analyses were conducted with NONMEM VI using standard model discrimination criteria. Covariate analyses were also performed using stepwise forward regression followed by backward deletion. RESULTS: After correction of Al exposure, serum levels declined in a biphasic manner, which was captured by the TK model. The TK of Al were best described by a 2-compartment model with linear elimination. Total creatinine clearance was a significant covariate for total clearance (CL). Mean parameter estimates for volume of central compartment (V1), CL, volume of peripheral compartment (V2), volume of distribution at steady-state (Vss), and intercompartmental clearance (Q) were 168 L, 8.99 L/day, 12 000 L, 12 168 L, and 4.93 L/day, respectively. Inter-individual variability for CL and V2 were 22.6 and 51.1%, respectively. Al distributional half-life was 8.5 days, while the terminal elimination half-life was 7.2 years. This model confirms that the large Vss reflects the widespread distribution of Al in bone, lungs, liver, and other tissues. CONCLUSION: This study describes the first population Al TK model in a large group of PD patients, which includes a covariate effect. The model confirms the extensive half-life and tissue distribution of Al in a dialysis-dependent population.

Successful treatment of lithium toxicity with sodium polystyrene sulfonate: a retrospective cohort study.

CONTEXT: Lithium (Li) is a first-line treatment for bipolar disorder but has a narrow therapeutic index. Treatment of Li toxicity includes supportive measures and hemodialysis in severe cases, but this modality is not always immediately available. Sodium polystyrene sulfonate (SPS, Kayexalate), a cation exchanger, has been promising in animal models and human reports to reduce absorption and enhance elimination of Li. MATERIAL AND METHODS: A retrospective cohort study was conducted. All cases of chronic Li intoxication were reviewed in two adult-care hospitals from 2000 to 2009. A group comparison and a within-patient comparison were performed to compare the effect of SPS on the median Li half-life (T(1/2)). For this study, at least three serum Li levels were required for T(1/2) calculations. RESULTS: Forty-eight patients met inclusion requirements, 12 of whom had taken SPS. Median Li T(1/2) in the treated and control groups was 20.5 and 43.2 hours, respectively (p = 0.0006). In the 12 treated patients, Li T(1/2) during SPS was on average 48.9% shorter than without SPS. Furthermore, in one subject in whom urinary Li data were available, Li clearance with SPS was superior to Li renal clearance. Prolonged constipation was noted in one patient whereas mild hypokalemia was noted in six patients treated with SPS. CONCLUSION: This study shows that SPS reduced Li T(1/2) and suggests that SPS is capable of promoting Li elimination in chronic intoxications. These results warrant a prospective trial looking at the use of SPS in the treatment of Li overdose as an adjunct to supportive measures and hemodialysis.