Nonlinear Pharmacokinetics Research Articles

Population pharmacokinetics of favipiravir in patients with COVID-19.

The antiretroviral drug favipiravir (FPV) inhibits RNA‐dependent RNA polymerase. It has been developed for the treatment of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infection disease, coronavirus disease 2019 (COVID‐19). However, its pharmacokinetics in patients with COVID‐19 is poorly understood. In this study, we measured FPV serum concentration by liquid chromatography–tandem mass spectrometry and conducted population pharmacokinetic analysis. A total of 39 patients were enrolled in the study: 33 were administered FPV 1600 mg twice daily (b.i.d.) on the first day followed by 600 mg b.i.d., and 6 were administered FPV 1800 mg b.i.d. on the first day followed by 800 mg or 600 mg b.i.d. The median age was 68 years (range, 27–89 years), 31 (79.5%) patients were men, median body surface area (BSA) was 1.72 m2 (range, 1.11–2.2 m2), and 10 (25.6%) patients required invasive mechanical ventilation (IMV) at the start of FPV. A total of 204 serum concentrations were available for pharmacokinetic analysis. A one‐compartment model with first‐order elimination was used to describe the pharmacokinetics. The estimated mean clearance/bioavailability (CL/F) and distribution volume/bioavailability (V/F) were 5.11 L/h and 41.6 L, respectively. Covariate analysis revealed that CL/F was significantly related to dosage, IMV use, and BSA. A simulation study showed that the 1600 mg/600 mg b.i.d. regimen was insufficient for the treatment of COVID‐19 targeting the 50% effective concentration (9.7 µg/mL), especially in patients with larger BSA and/or IMV. A higher FPV dosage is required for COVID‐19, but dose‐dependent nonlinear pharmacokinetics may cause an unexpected significant pharmacokinetic change and drug toxicity. Further studies are warranted to explore the optimal FPV regimen.

A Target-Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults.

SPI‐62 is a selective and potent small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1). SPI‐62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose‐dependent volume of distribution, nonlinear PK following the first dose, and dose‐proportional PK at steady state, as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI‐62 is the saturable binding of SPI‐62 to its pharmacological target HSD‐1, a phenomenon known as target‐mediated drug disposition (TMDD). Because of the nonlinear and complex PK of SPI‐62, the relationship among SPI‐62 dose, exposure, and response is no longer intuitive and consequently dose selection can be challenging. To facilitate dose selection and clinical trial design, in the current study population PK analysis was performed to characterize SPI‐62 dose‐exposure relationship in humans quantitatively. SPI‐62 PK was best characterized by a 2‐compartment TMDD model with 3 transit absorption compartments. The model was successfully established to explain the substantial and unusual nonlinear PK of SPI‐62 in humans, and it provided adequate fitting for both single‐ and multiple‐dose data. Our modeling work has provided a strong foundation for dose selection in future SPI‐62 clinical trials.

Abstract 1797: Preclinical characterization of Sym024, a novel anti-CD73 antibody

Abstract Tumor cells are surrounded by a complex microenvironment (the tumor microenvironment, or TME) that influences each step of tumorigenesis. In the TME, increased concentrations of immune modulating factors such as adenosine help tumor cells evade host anti-tumor immune responses. Adenosine binds to adenosine receptors (ARs) expressed on various immune cells such as CD4+ and CD8+ T cells, myeloid cells and natural killer (NK) cells. These receptors exhibit distinct properties and cell and tissue distribution. Binding of adenosine to a subset of ARs suppresses the anti-tumor responses of T cells and NK cells and augments the activity of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells, thus promoting tumor progression. The generation of adenosine in the TME is mediated by a group of ectonucleotidases, including CD39 and CD73, which work in a common pathway converting extracellular ATP to adenosine. CD73 is frequently overexpressed on human tumor cells and mediates the hydrolysis of AMP to adenosine, particularly under hypoxic conditions. Importantly, CD73 overexpression correlates with poorer prognosis in various cancers, including lung, gastric, head and neck, pancreatic, cholangiocarcinoma, colorectal, bladder, triple negative breast, ovarian, and kidney cancer, and melanoma. Inhibition of the enzymatic activity of CD73 therefore represents an attractive way of relieving the immune suppressive activity of adenosine in the TME.Sym024 is an Fc-attenuated human monoclonal antibody that binds to human and cynomolgus monkey CD73 with sub-nanomolar avidity. Sym024 binds to a distinct epitope on the enzyme on the opposite side relative to the catalytic center and potently inhibits the activity of soluble CD73 as well as CD73 expressed on numerous cancer cell lines and primary lymphocytes. Importantly, CD73 inhibition by Sym024 alleviates AMP-mediated inhibition of T cell proliferation and activation. In vitro one-way mixed lymphocyte reaction results demonstrate the utility of combining CD73 inhibition with PD-1 blockade, as Sym024 acts to reverse the immune suppressive effect of adenosine production, thereby allowing effective T cell activation by an anti-PD-1 antibody (Sym021). Mechanistically, Sym024 inhibits cellular CD73 by direct enzymatic inhibition with moderate shedding or degradation of CD73 in vitro. In preclinical in vivo tumor models, Sym024 effectively inhibits CD73 activity and tumor growth. Sym024 was well tolerated with no observed toxicity in repeat dose studies in monkeys at dose levels up to 100 mg/kg. Dose-proportional and linear pharmacokinetics (PK) was observed at high dose levels while nonlinear PK became evident at lower exposure levels. Sym024 is currently under clinical investigation. Citation Format: Janus S. Jakobsen, Matteo Riva, Maria C. Melander, Randi W. Hansen, Klaus Kofoed, Mikkel W. Pedersen, Jutta Deckert, Lene Hansen, Niels Jorgen Skartved, Johan Lantto, Camilla Frohlich, Michael Monrad Grandal. Preclinical characterization of Sym024, a novel anti-CD73 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1797.

Prediction of Non-Linear Pharmacokinetics of Monoclonal Antibodies in Human from Nonclinical Data: Are We There Yet?

Prediction of Non-Linear Pharmacokinetics of Monoclonal Antibodies in Human from Nonclinical Data: Are We There Yet?

Exposures of Phenylacetic Acid and Phenylacetylglutamine Across Different Subpopulations and Correlation with Adverse Events.

BackgroundElevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the l-ornithine salt of phenylacetate, is under development for hepatic encephalopathy.ObjectiveThis analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program.MethodsPhenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child–Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis.ResultsPhenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child–Pugh C than in Child–Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy.ConclusionsDose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01047-5.

Pharmacokinetics of genistein distribution in blood and retinas of diabetic and non-diabetic rats

Genistein, a natural tyrosine kinase inhibitor, may act as an intraocular antiangiogenic agent. Its therapeutical use, however, is limited by its nonlinear pharmacokinetics. We aimed to determine genistein's kinetics and retinal tissue distributions in normal and diabetic rats. We developed an isocratic, reverse-phase C18 HPLC system to measure genistein concentration in blood and retinas of streptozotocin (65 mg/kg IV)-diabetic and non-diabetic rats receiving two types of genistein-rich diet (150 and 300 mg/kg) for ten days. Genistein's decay exhibited a two-compartmental open model. Half-lives of distribution and elimination were 2.09 and 71.79 min, with no difference between groups. Genistein steady-state concentration in blood for 150 and 300 mg/kg diet did not differ between diabetic (0.259 ± 0.07 and 0.26 ± 0.06 μg/ml) and non-diabetic rats (0.192 ± 0.05 and 0.183 ± 0.09 μg/ml). In retina, genistein concentration was significantly higher in diabetic rats (1.05 ± 0.47 and 0.997 ± 0.47 μg/gm wt. vs. 0.087 ± 0.11 and 0.314 ± 0.18 μg/gm wt., p < 0.05). The study determined that increasing genistein dose did not change its bioavailability, perhaps due to the poor aqueous solubility. The retina's increased genistein could be due to increased permeability of blood-retinal barrier that occurs early in diabetes.

Target‐mediated drug disposition modeling of an anti‐TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics

BackgroundMG1113 is a human monoclonal antibody of tissue factor pathway inhibitor (TFPI) under development for prophylaxis for hemophilia patients with or without inhibitors against factor VIII products, which have been used for the treatment of hemophilia. Because TFPI is a negative regulator in the extrinsic coagulation pathway, neutralization of TFPI function by MG1113 can potentially increase coagulation activity by bypassing the intrinsic coagulation pathway, which factor VIII activates. ObjectivesThis study aims to determine the correlation between pharmacokinetics (PK) and pharmacodynamics (PD) after administering MG1113 to monkeys and to predict the PK and PD of MG1113 in humans by the Target‐Mediated Drug Disposition (TMDD) model using the results from monkeys. MethodsThe PK profile of MG1113 and the PD effect on the free TFPI level were evaluated after intravenous (IV) and subcutaneous (SC) administrations of MG1113 (2.5, 5, and 10 mg/kg) to male cynomolgus monkeys. After setting up the PK/PD model on monkeys, PK parameters on humans were calculated using allometric scaling, and then clinically effective doses were predicted applying the TMDD model. Results and ConclusionsMG1113 showed nonlinear PK after both IV and SC administrations at the dosing range from 2.5 to10 mg/kg. The concentrations of MG1113 versus TFPI could be characterized a dose‐response relationship using a TMDD model. The TMDD modeling and simulation built in this study were used to simulate various dosage regimens of MG1113 to apply to the first‐in‐human study design, and moreover expected to be referred to establish the dose for further clinical trials.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

Personalized Medication and Activity Planning in PDDL+

The emergence of planners capable of reasoning with continuous dynamics, as expressed in PDDL+, has increased the range of problems that fall within the capabilities of PDDL planners. One such problem is planning patients’ activities and medication regimes, considering non-linear medication pharmacokinetics. In this paper we explore the application of contemporary PDDL+ planners to this problem. To address their performance limitations, we present a linearize–validate cycle; tasks are solved by iterative refinement of a linear approximation of the domain, solved by a linear planner, then validated at each stage against the full non-linear semantics. In doing this we allow this domain to fall within the capabilities of current planners; and in our evaluation we use OPTIC to demonstrate this.

Analysis of Non-linear Pharmacokinetics of P-Glycoprotein Substrates in a Microfluidic Device Using a Mathematical Model that Includes an Unstirred Water Layer (UWL) Compartment

The purpose of this research is to analyze non-linear pharmacokinetics of P-glycoprotein (P-gp) substrates in a cell based assay of a microfluidic device, which might be affected by hydrodynamic barrier (unstirred water layer, UWL). Apparent permeability (Papp) were obtained using non-P-gp substrates (propranolol, metoprolol, and atenolol) and P-gp substrates (quinidine and talinolol) in a commercially available microfluidic device, organoplate ® of Caco-2 cell based assay. The previous UWL resistance model was well fitted to Papp of static and flow condition by assuming UWL including and negligible condition, while P-gp substrates of higher passive permeability (quinidine) was apart from the fitting curve. The concentration dependent non-linear kinetics of P-gp substrates, quinidine and talinolol, was more analyzed in detail, and apparent Vmax discrepancybetween static and flow assay condition in the quinidine assay was observed, while that was not observed in talinolol, the lower permeable substrate. Based on the experimental results, a mathematical model for P-gp substrates including UWL compartment on the previous 3-compartment model was developed, and it indicated that the apparent Vmax was variable along with the ratio between passive permeability and UWL permeability. The mathematical model adding UWL compartment well explained non-linear pharmacokinetics of apparent permeability of P-gp substrate in the microfluidic device. The model also has a potential to be applied to P-gp substrate permeability analysis in vivo.

Estimation of Clearance and Bioavailability of Therapeutic Monoclonal Antibodies from Only Subcutaneous Injection Data in Humans Based on Comprehensive Analysis of Clinical Data

IntroductionTheoretically, the separate estimation of clearance (CL) and bioavailability (F) requires both intravenous and extravascular injection data. This study investigated whether CL and subcutaneous F of therapeutic monoclonal antibodies (mAbs) in humans can be separately estimated from subcutaneous injection data only.MethodsFirst, the geometric mean of linear pharmacokinetic parameters (CL, intercompartmental CL [Q], volume of distribution in the central compartment [Vc], and volume of distribution in the peripheral compartment [Vp]) after intravenous injection for mAbs in humans that have been reported in public data sources was estimated from 103 mAbs with linear pharmacokinetics and 44 mAbs with nonlinear pharmacokinetics. Next, we estimated the CL and F of 25 mAbs with linear pharmacokinetics from plasma/serum mAb concentration–time profiles after subcutaneous injection in humans by fixing the geometric mean of Q, Vc, and Vp based on the public data. Moreover, the plasma/serum concentration–time profile of 25 mAbs after intravenous injection was simulated using the estimated CL and the geometric mean of Q, Vc, and Vp.ResultsThere were no significant differences in parameters among subclasses (immunoglobulin [Ig] G1, 2, and 4) or in linearity (derivation from linear and nonlinear pharmacokinetics). Using only subcutaneous injection data, we successfully estimated the CL of 23/25 mAbs (92%) and F of all 25 mAbs (100%) within 1.5-fold of the observed value. Moreover, overall, the simulated concentration–time profiles were largely consistent with observed data (90.8% within 1.5-fold of the observed values).ConclusionsThis approach does not require intravenous injection data to separately estimate CL and F after subcutaneous injection in humans and can therefore accelerate the clinical development of mAbs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01023-z.

Pharmacokinetics and Determination of Tumor Interstitial Distribution of a Therapeutic Monoclonal Antibody Using Large-Pore Microdialysis.

R7072 is a fully human monoclonal antibody (mAb) exerting anti-tumor activity via blockade of insulin like growth factor 1 receptor. The tumoral interstitial concentrations are anticipated to be better surrogates of active site concentrations than commonly used serum concentrations for pharmacokinetic-pharmacodynamic correlation of anti-tumor mAbs. Previously, a large-pore microdialysis technique for measuring tissue interstitial concentrations of R7072 in non-tumor bearing mice was established. In the current studies, the serum pharmacokinetics of R7072 were assessed and tissue interstitial concentrations were measured by large-pore microdialysis following intravenous and intraperitoneal administration of R7072 in tumor bearing mice. R7072 exhibited nonlinear pharmacokinetics in the studied dose range. Tumor and subcutaneous interstitial concentration data suggested some delay in tissue distribution after dosing. A dose-dependent increase in the ratio of tumor interstitial to serum concentration was observed indicating target-mediated drug disposition in tumor tissue. However, subcutaneous interstitial to serum concentration ratios were similar across the doses as observed previously in non-tumor bearing mice. A two-compartment population pharmacokinetic model with subcutaneous and tumor as open-loop compartments comprising of parallel linear and non-linear elimination from serum, linear disposition from subcutaneous interstitium and non-linear disposition from tumor interstitium was developed to simultaneously describe the pharmacokinetic data from all matrices.

Planning and Evaluation of Bioequivalence Studies of Drugs with Nonlinear Pharmacokinetics

A bioequivalence (BE) study is one of the key stages of investigations required for the registration of oral generic drugs. The planning of this type of study is determined by many factors, including the linearity of the pharmacokinetics of the active substance. The choice of the drug dose for a BE study will depend on this property in registering several drug strengths. Regulatory requirements for planning BE studies of drugs with non-linear pharmacokinetics are considered using atazanavir and valaciclovir as examples. An analysis of protocols and reports of BE studies received by the SCEEMP according to the State Drug Registry and open published data on BE revealed differences in both the tested drug dosages and the number of tests performed. All characteristics of the given active substance, available literature data, international experience, and current regulatory requirements should be taken into account in planning and evaluating BE studies of drugs with non-linear pharmacokinetics.

Population pharmacokinetic analysis of RO5459072, a low water-soluble drug exhibiting complex food-drug interactions.

AimsRO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis.MethodsPK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling.ResultsThe PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase.ConclusionThe population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.

Pharmacokinetics of rifampicin after repeated intra-tracheal administration of amorphous and crystalline powder formulations to Sprague Dawley rats

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.

Revisiting Nonlinear Bosentan Pharmacokinetics by Physiologically Based Pharmacokinetic Modeling: Target Binding, Albeit Not a Major Contributor to Nonlinearity, Can Offer Prediction of Target Occupancy.

Bosentan is a high-affinity antagonist of endothelin receptors and one of the earliest examples for target-mediated drug disposition [a type of nonlinear pharmacokinetics (PKs) caused by saturable target binding]. The previous physiologically based PK (PBPK) modeling indicated that the nonlinear PKs of bosentan was explainable by considering saturable hepatic uptake. However, it remained unexamined to what extent the saturable target binding contributes to the nonlinear PKs of bosentan. Here, we developed a PBPK model incorporating saturable target binding and hepatic uptake and analyzed the clinical bosentan PK data using the cluster Gauss-Newton method (CGNM). The PBPK model without target binding fell short in capturing the bosentan concentrations below 100 nM, based on the PK profiles and the goodness-of-fit plot. Both global and local identifiability analyses (using the CGNM and Fisher information matrix, respectively) informed that the target binding parameters were identifiable only if the observations from the lowest dose (10 mg) were included. By analyzing blood PK profiles alone, the PBPK model with target binding yielded practically identifiable target binding parameters and predicted the maximum target occupancies of 0.6-0.8 at clinical bosentan doses. Our results indicate that target binding, albeit not a major contributor to the nonlinear bosentan PKs, may offer a prediction of target occupancy from blood PK profiles alone and potential guidance on achieving optimal efficacy outcomes, under the condition when the high-affinity drug target is responsible for the efficacy of interest and when the dose ranges cover varying degrees of target binding. SIGNIFICANCE STATEMENT: By incorporating saturable target binding, our physiologically based pharmacokinetic (PBPK) model predicted in vivo target occupancy of bosentan based only on the blood concentration-time profiles obtained from a wide range of doses. Our analysis highlights the potential utility of PBPK models that incorporate target binding in predicting target occupancy in vivo.

Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non-Small-Cell Lung Cancer.

PURPOSEMET dysregulation is an oncogenic driver in non–small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor (EGFR)–mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance.METHODSA standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination.RESULTSThe most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%.CONCLUSIONCapmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.

DETERMINATION OF PHARMACOKINETIC PARAMETERS AND FACTORS INFLUENCING THE PHARMACOKINETIC PARAMETERS OF PHENYTOIN IN THAI CHILDREN WITH EPILEPSY

Objective: Phenytoin displays nonlinear pharmacokinetics due to the saturation of its’ metabolizing enzymes, thus making dosing adjustments a challenge in clinical practice. However, data on the pharmacokinetic parameters of phenytoin in pediatric patients with epilepsy in Thailand remain lacking. This study aimed to determine the pharmacokinetic parameters of phenytoin, and the factors influencing them in epileptic Thai children using therapeutic drug monitoring data.&#x0D; Methods: Steady state phenytoin plasma concentrations were collected from 96 Thai children with epilepsy aged ≤ 15 y. For individuals having a single steady-state concentration (Css) on one dosage, the Vmax was determined by fixing Km = 4.5 mg/l. For patients with two values for Css with different dosages, the Ludden method was used to determine Vmax and Km. Influences on Vmax and Km by demographic factors including age, sex, weight, serum albumin, and the use of CYP2C9 inducers (carbamazepine, phenobarbital, folic acid, and vigabatrin) and inhibitors (valproic acid and topiramate) were determined by linear mixed-effects regression.&#x0D; Results: The majority of patients had sub-therapeutic plasma concentrations of phenytoin. The Vmax and Km were estimated to be 9.84 mg/kg/d and 2.32 mg/l, respectively. Age and weight significantly influenced Vmax, whereas Km had no significant influencing factors.&#x0D; Conclusion: The Vmax estimated in this study is different from other populations previously reported. Our results suggest that increased phenytoin dosages may be required to achieve optimal concentrations due to the sub-therapeutic concentrations reported here. The results from this study are beneficial for phenytoin dosage individualization in Thai children.

A sensitive HPLC-FLD method for the quantification of alpelisib, a novel phosphatidylinositol 3-kinase inhibitor, in rat plasma: Drug metabolism and pharmacokinetic evaluation in vitro and in vivo

Alpelisib, a novel phosphatidylinositol 3-kinase inhibitor, is an oral anticancer agent approved for the treatment of advanced or metastatic breast cancer. In this study, a sensitive bioanalytical method using high-performance liquid chromatography combined with a fluorescence detector (HPLC-FLD) was developed for the determination of alpelisib in rat plasma. This newly developed method was validated in terms of linearity (1–1,000 ng/mL), precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guideline and these parameters were within the acceptable limits. Alpelisib tended to be stable in plasma, urine, simulated intestinal fluid, and buffer with pH > 4.0 for 24 h, but in the pH 1.2 buffer and simulated gastric fluid for up to 4 h only. A study involving intravenous administration of alpelisib in rats showed that the dose-normalized area under the plasma concentration versus time curve (AUC) of alpelisib changed significantly as the dose increased from 1 to 10 mg/kg. Similarly, an oral rat study indicated that the dose-normalized AUC and the fraction of dose that remained in the gastrointestinal (GI) tract changed significantly as the dose increased from 0.5 to 10 mg/kg. These nonlinear (dose-dependent) pharmacokinetics of intravenous and oral alpelisib could be attributed to the saturation of ubiquitous metabolism among most tissues and/or GI absorption processes. To the best of our knowledge, this is the first study to investigate the in vivo nonlinear pharmacokinetics of alpelisib and its possible mechanisms, together with a new HPLC-FLD method to determine alpelisib in biological matrices.

Pharmacokinetics, pharmacodynamics, and safety of subcutaneous anifrolumab in patients with systemic lupus erythematosus, active skin disease, and high type I interferon gene signature: a multicentre, randomised, double-blind, placebo-controlled, phase 2 study.

300 mg of intravenous anifrolumab every 4 weeks added to standard-of-care treatment for patients with systemic lupus erythematosus (SLE) reduced disease activity and glucocorticoid requirement in a previous phase 3 trial. Because patients might find subcutaneous administration more convenient than intravenous delivery, we aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous anifrolumab in patients with SLE, active skin disease, and a high type I interferon gene signature. This multicentre, randomised, double-blind, placebo-controlled, phase 2 study was done at 12 hospitals and outpatient clinics in Hungary, South Korea, Poland, and the USA. Eligible patients were aged 18-70 years, and had SLE with high type I interferon gene signature and an activity score on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) of at least 10. Enrolled participants were randomly assigned (3:1:3:1) by use of a voice-web response system to receive either 150 mg of subcutaneous anifrolumab or corresponding placebo, or 300 mg of subcutaneous anifrolumab or corresponding placebo in addition to stable standard-of-care treatment. The study was double-blinded with respect to intervention but not dose, until 12 weeks. Doses of oral glucocorticoids were tapered after week 12. The primary pharmacokinetic endpoint was the serum concentration of anifrolumab based on the maximum concentration after the first dose and the minimum (trough) concentration before subsequent doses and was measured in all patients who received anifrolumab and had at least one quantifiable serum pharmacokinetics observation following the first dose. The primary pharmacodynamic endpoint was neutralisation of the type I interferon pharmacodynamic signature at week 12 and was assessed in all patients with a high type I interferon pharmacodynamics signature at baseline based on a 21-gene test. Safety was evaluated in the full analysis set, which included all patients who received at least one dose of anifrolumab. This trial is completed and is registered at ClinicalTrials.gov, NCT02962960. Between March 14, 2017, and Oct 26, 2017, 36 patients were randomly assigned to receive 150 mg of anifrolumab (n=14), 300 mg of anifrolumab (n=13), or placebo (n=9). Two patients in the anifrolumab 150 mg group were excluded from the pharmacodynamic analysis set (n=34). Ten (71%) of 14 patients in the anifrolumab 150 mg group, ten (77%) of 13 patients in the anifrolumab 300 mg group, and nine (100%) of the nine patients in the placebo group completed 52 weeks of treatment. At week 12, pre-dose mean trough serum concentrations of anifrolumab were more than dose proportional between the anifrolumab 150 mg group (19·82 μg/mL [SD 15·01]) and the anifrolumab 300 mg group (60·28 μg/mL [43·66]), and the pharmacokinetics were non-linear. At week 12, the median percentage neutralisation of the type I interferon gene signature was higher with 150 mg (88·0% [median absolute deviation 7·4]) and 300 mg (90·7% [3·3]) of anifrolumab than with placebo (18·5% [8·1]), and more patients in the anifrolumab 150 mg group and the anifrolumab 300 mg group than in the placebo group had neutralisation of 75% or more (eight [67%] of 12 vs ten [77%] of 13 vs one [11%] of nine). At least one adverse event was reported by 23 (85%) of 27 patients in the anifrolumab groups and by seven (78%) of nine patients in the placebo group; most adverse events were of mild-to-moderate severity. Serious adverse events were reported in six (22%) of 27 patients in the anifrolumab groups (four patients in the 150 mg group and two in the 300 mg group). No serious adverse events were reported in the placebo group. Herpes zoster infection was reported by three (11%) of 27 patients in the anifrolumab groups and by one (11%) of nine patients in the placebo group. There were no treatment-related deaths. Anifrolumab, administered subcutaneously every 2 weeks to patients with SLE and moderate-to-severe skin manifestations, had non-linear pharmacokinetics that were more than dose proportional, and neutralised the type I interferon gene signature in a dose-dependent manner. The safety profile was consistent with previous studies of intravenous anifrolumab, supporting the continued development of anifrolumab as a subcutaneously administered therapy for patients with SLE. AstraZeneca.