Clinical Pharmacokinetics

Population-Pharmacokinetic Modeling of Tildrakizumab (MK-3222), an Anti-Interleukin-23-p19 Monoclonal Antibody, in Healthy Volunteers and Subjects with Psoriasis Abstract Background Tildrakizumab is an anti-interleukin-23p19 monoclonal antibody recently approved for the treatment of chronic plaque psoriasis. Methods This analysis characterizes the population pharmacokinetics of subcutaneous tildrakizumab and identifies covariates influencing exposure in 2098 healthy volunteers and subjects with psoriasis. Tested covariates included body weight, formulation type, sex, age, race, serum albumin, creatinine clearance, Japanese origin, prior treatment with a biologic agent, subject status (subjects with psoriasis vs. healthy volunteers), and ethnicity. Results The pharmacokinetics was described by a one-compartment model with first-order absorption and elimination kinetics, and inter-individual variability on clearance, volume of distribution, and absorption rate constant. The pharmacokinetics was characterized by low clearance and limited volume of distribution. In subjects with psoriasis, the geometric mean clearance (coefficient of variation) was 0.32 L/day (38%), volume of distribution was 10.8 L (24%), and absorption and elimination half-life were 1.5 days (18%) and 23.4 days (23%), respectively, with an absorption lag time of 1.2 h. For the 100-mg dose, steady-state area under the plasma concentration vs. time curve for one dosing interval and maximum plasma concentration were 305 µg*day/mL (41%) and 8.1 µg/mL (34%), respectively. Steady state was achieved by 16 weeks with the clinical regimen (dosing on week 0 and week 4 and every 12 weeks thereafter) with 1.1-fold accumulation in maximum plasma concentration. Healthy subjects had 31% higher bioavailability than subjects with psoriasis. Subjects with increased body weight had a lower area under the plasma concentration-time curve at steady state vs. those with lower body weight. The modeled exposures were contained within clinical comparability bounds for all covariates including body weight. Conclusions The pharmacokinetics of tildrakizumab behaves like a typical monoclonal antibody without requiring dosage adjustment. Trial Registration NCT01729754, NCT01225731, NCT01722331.

Population Pharmacokinetics of Upadacitinib Using the Immediate-Release and Extended-Release Formulations in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I–III Clinical Trials Abstract Background and Objectives Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I–III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations. Methods Pharmacokinetic data from 4170 subjects taking IR doses of 1–48 mg and ER doses of 7.5–30 mg across 12 studies spanning phase I–III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks. Results A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration–time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration–time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60–100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure. Conclusions A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I–III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure–response relationship of upadacitinib.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment Abstract Introduction Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. Methods A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child–Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. Results Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. Conclusions No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the (Modern) Treatment of Melanoma Abstract Targeted therapies, based on identification of common oncogenic mutations such as BRAF V600E/K and monoclonal antibody immunotherapies, have transformed the treatment of melanoma. Dual mitogen-activated protein kinase (MAPK) pathway inhibition of BRAF V600E/K and MEK 1/2 kinases with BRAF–MEK inhibitors using dabrafenib–trametinib, vemurafenib–cobimetinib and encorafenib–binimetinib is now the standard of care for BRAF V600E/K tumours. Monoclonal antibodies, such as pembrolizumab and nivolumab, against programmed cell death protein (PD-1) on T cells, as well as ipilimumab against cytotoxic T lymphocyte antigen-4 (CTLA-4), enable restoration of suppressed T-cell antitumour response, and have also shown improved clinical benefit compared with traditional chemotherapy. Exploration of different combination therapies, sequence of treatment, and dosing strategies is ongoing, and the understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of these new agents is fundamental in devising the optimal regimen. Preclinical and clinical studies, as well as population PK modelling, provide essential data in terms of PK parameters, metabolism, interpatient variability, drug interactions and PD effects at the target. This review gathers the current evidence and understanding of the clinical PK and PD of drugs used in the modern treatment of melanoma, and the factors determining drug disposition, exposure and clinical response, and also highlighting areas of further research.

Unbound Fraction of Clozapine Significantly Decreases with Elevated Plasma Concentrations of the Inflammatory Acute-Phase Protein Alpha-1-Acid Glycoprotein Abstract Background During inflammation, elevated total (unbound plus protein-bound) clozapine plasma concentrations have been observed. Elevated alpha-1-acid glycoprotein concentrations during inflammation are suggested to cause increased plasma clozapine-alpha-1-acid glycoprotein binding, resulting in elevated total clozapine plasma concentrations without significant changes in unbound concentrations. Here, we investigated the association between alpha-1-acid glycoprotein plasma concentrations and clozapine unbound fraction. Methods First, 25 and 60 µL of alpha-1-acid glycoprotein solution (20 mg/mL) were added to plasma samples (n = 3) of clozapine users (spiking experiment). Second, the association between alpha-1-acid glycoprotein plasma concentration and clozapine unbound fraction was assessed in patient samples (patient study). Samples were determined by liquid chromatography-tandem mass spectrometry. Data were analyzed with a paired t test (spiking experiment) and an unpaired t test (patient study). Results The spiking experiment showed significantly lower mean unbound fractions following 25- and 60-µL alpha-1-acid glycoprotein spikes (relative reductions of 28.3%, p = 0.032 and 43.4%, p = 0.048). In the patient study, total clozapine plasma concentrations were 10% higher in elevated (n = 6) compared with normal alpha-1-acid glycoprotein (n = 20) samples [525 µg/L vs. 479 µg/L, mean difference = 47 µg/L (95% confidence interval −217 to 310), p = 0.72]. Elevated alpha-1-acid glycoprotein samples had a 26% lower mean unbound fraction compared with normal samples [1.22% vs. 1.65%, mean difference = −0.43% (95% confidence interval −0.816 to −0.0443), p = 0.03]. Conclusions Both the spiking experiment and patient study showed a significant association between elevated alpha-1-acid glycoprotein plasma concentrations and a lower clozapine unbound fraction. Future studies should include clinical data to examine whether this association is clinically relevant, suggesting any clozapine dose adjustments.

Revisiting the Pharmacology of Unfractionated Heparin Abstract Unfractionated heparin (UFH) is a commonly used anticoagulant therapy for the acute treatment and prevention of thrombosis. Its short duration of action, reversibility of effect by protamine sulfate, and extensive clinical experience are some of the advantages that support its use. However, the choice of dose and dosing regimen of UFH remains challenging for several reasons. First, UFH has a narrow therapeutic window and wide variability in the dose–response relationship. Second, its pharmacodynamic (PD) properties are difficult to characterise owing to the complex multidimensional mechanisms of interaction with the haemostatic system. Third, the complex heterogeneous chemical composition of UFH precludes precise characterisation of its pharmacokinetic (PK) properties. This review provides a comprehensive mechanistic approach to the interaction of UFH with the haemostatic system. The effect of chemical structure on its PK and PD properties is quantitatively described, and a framework for characterisation of the dose–response relationship of UFH for the purpose of dose optimisation is proposed.

Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma Abstract The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations Abstract Background Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. Methods Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. Results Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 μg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 −1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 −1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. Conclusions Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

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