Population Pharmacokinetic Approach Research Articles

Model-Informed Clinical Development of 6-Monthly Injection of Paliperidone Palmitate in Patients with Schizophrenia: Dosing Strategies Guided by Population Pharmacokinetic Modeling and Simulation (Part II).

Paliperidone palmitate 6-month (PP6M) intramuscular (IM) injection is the longest-acting treatment available for patients with schizophrenia. A population pharmacokinetic (popPK) modeling and simulation approach was deployed to inform dosing strategies for PP6M. The extensive analysis database included 15,932 paliperidone samples from 700 patients receiving gluteal paliperidone palmitate 3-month (PP3M) or PP6M injections in the double-blind phase of a phase-3 noninferiority study (NCT03345342). Exposure parameters for paliperidone appeared to increase dose-proportionally within each dosing schedule (PP3M/PP6M). The range of paliperidone exposures after IM administration of PP6M overlaps with that of corresponding doses of oral paliperidone extended release, PP 1-month (PP1M), and PP3M. Model-based simulations were performed to investigate paliperidone exposures in different PP6M dosing scenarios and relevant subpopulations. A dosing window of ≤ 2 weeks earlier and ≤ 3 weeks later than the target 6-month interval for maintenance treatment with PP6M dosing maintains paliperidone exposures at levels that are not expected to substantially impact its safety and efficacy. For missed-dose scenarios, tailored re-initiation regimens are proposed that should be applied before resuming PP6M maintenance dosing. Regarding subpopulations, PP6M 700 mg eq. is the highest dose recommended in mild renal-impairment patients; the paliperidone pharmacokinetics after PP6M administration is not affected by sex, body mass index, or age in a clinically meaningful way. Paliperidone concentration-time profiles after PP6M and PP3M dosing were adequately described by the popPK model. Model-based simulation results provide guidance for clinicians on initiating PP6M therapy, transitioning between paliperidone formulations, the dosing windows to use for maintenance dosing, and managing missed PP6M doses.

Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy. Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software. Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT >MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT >MIC. Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2g may insufficient to achieve 70% fT >MIC in septic patients. The dosage regimen of 600mg every 6h appears to be the optimal choice.

Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients

Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients

Optimization of vigabatrin dosage in children with epileptic spasms: A population pharmacokinetic approach.

Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response. We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range. We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC0-24 between 264 and 549 mg.h.L-1. The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients.

Factors Influencing Serum Posaconazole Concentrations in Patients with Hematologic Malignancies Receiving Delayed-Release Tablets.

Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity (P = 0.188). We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.

Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail.

Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail. Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination. A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29h-1 vs. 5.18h-1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40µmol/h at the median absolute estimated glomerular filtration rate of 105mL/min. The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used.

Integrating Full Bayesian Inference and Student's t-Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug-Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients.

As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP)enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field.

Pharmacokinetics of drugs used to treat drug sensitive-tuberculosis in breastfeeding mother-infant pairs: An observational pharmacokinetic study

Background Globally, more than half of women take medicines whilst breastfeeding. Data concerning the exposure of the breastfed infant to drugs and any related risks are sparce. Lactation studies are only rarely performed close to licensing for medicines anticipated to be widely used in women of childbearing age. Medicines taken by breastfeeding mothers on tuberculosis (TB) treatment can be transferred to the breastfed infant. Potential effects of anti-tuberculosis medicines on nursing infants are not well understood. Similarly, women face mental health challenges whilst taking medications, including postpartum depression, hence the need to assess the psychological behavior of a breastfeeding woman. Potential risks are the development of adverse drug effects in the breastfed infant and selection for resistance, whereas potential benefits might include exposure to potentially prophylactic concentrations of the drug. Pharmacokinetic studies are therefore necessary to understand this situation fully. Methods This study will enroll 20 mothers receiving first-line anti-tuberculosis medicines, together with their breastfed infants, with the aim of characterizing the breastmilk transfer of the medicines from the mother to the infants. Samples of maternal blood, breastmilk and breastfeeding infant’s blood will be obtained at specific time points for bioanalysis of drug concentrations. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Additionally, the study will assess the psychological status of breastfeeding women and the well-being of their infants. Maternal depression is linked to long-term negative consequences for the infant’s physiological regulation, poor growth-promoting setting for the infants, and inappropriate interactive conduct, characterized by low compassion, constrained range of emotional expression, and varying provision of the infant’s budding engagement. Conclusions This study will provide the first systematic characterization of mother-to-infant transfer of first-line anti-tuberculosis medicines through breast milk. A mathematical pharmacokinetics model characterizing plasma-to-breastmilk transfer of rifampicin, isoniazid, ethambutol, and pyrazinamide will be developed and used to characterize infant exposure through breast milk. Our findings will contribute towards treatment optimization in breastfeeding and provide a framework to foster other lactation pharmacokinetic studies.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.

Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax /CL) ranged from 144.7 to 759.7mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.

Clofazimine pharmacokinetics in HIV-infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics.

Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea-associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)-infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea-associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV-infected adults with/without Cryptosporidium infection using nonlinear mixed-effects modeling. Covariates describing cryptosporidiosis-associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two-compartment model with lag time and first-order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h-1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

Fludarabine Lymphodepletion Exposure Is Associated with Idecabtagene Vicleucel Toxicity in Relapsed and Refractory Multiple Myeloma Patients: Real-World Experience from the US Myeloma Immunotherapy Consortium

Background. Idecabtagene vicleucel (ide-cel) is an anti-B-cell maturation antigen (BCMA) CAR-T associated with durable responses in relapsed/refractory multiple myeloma (RRMM) patients. Fludarabine (Flu), part of standard lymphodepleting chemotherapy (LDC), improves T-cell expansion and persistence, but BSA dosing results in significant pharmacokinetic (PK) variability. Flu exposure, defined by the area under the curve (AUC), has been shown to predict rates of relapse after anti-CD19 CAR-T in B-cell acute lymphoblastic leukemia (Fabrizio et al, Blood Advances 2022). We hypothesized Flu AUC may predict outcomes after ide-cel and, using a published population model (Langenhorst et al, Clin Pharmacokinet 2019 ) we assessed the impact of Flu AUC on standard-of-care (SOC) ide-cel outcomes. Methods. RRMM patients receiving SOC ide-cel from 11 of the US Myeloma Immunotherapy Consortium centers were retrospectively analyzed. FluCy was given on days -5 to -3 before CAR-T infusion. Patients were excluded if they did not receive FluCy LDC or ide-cel infusion, had ESRD on hemodialysis, or did not have creatinine values on LDC days. A population PK approach using cumulative Flu dose and PK covariates, eGFR and body weight (BW), was used to calculate C max and AUC 0-72h. PK parameters were first tested as continuous variables in univariable and multivariable (MV) analysis. ORs are expressed per 1 mg * hr/L in the model. Results. 285 patients were included with a median follow-up of 8.7 (4.3-14.2) months. eGFR distribution indicated large variability (mean=86.5 ml/min, CV 38.4%), with 151 (53%) having renal dysfunction (eGFR &amp;lt;90 ml/min/1.73). BW ranged from 42 to 147.2 kg. Wide PK variability was observed with a median Flu AUC of 19.01 (11.23-41.47) mg * h/L (Fig 1). When adjusted for high-risk features including high risk cytogenetics, extramedullary disease, exposure to BCMA agents, and receipt of bridging therapy in a MV model, Flu AUC was not found to be associated with efficacy, including overall response and progression free survival. However, when adjusted for bridging therapy response and prior lines of therapy as an indicator of disease status/burden pre-CAR-T, each 1 mg * h/L increment in Flu AUC was found to be associated with maximum grade &amp;gt;/= 2 cytokine release syndrome (CRS) (OR 1.083; 95% CI 1.013-1.160; p=0.020). While there was no difference in the occurrence of Grade 3/4 cytopenias, each 1 mg * h/L increment in Flu AUC was significantly associated with use of stem cell boost (OR 1.130; 95% CI 1.038-1.235; p=0.005). Discussion. In this real-world dataset of ide-cel treated RRMM patients, Flu exposure was found to have a significant association with severe CRS and need for stem cell boost. This is consistent with prior studies (Hirayama et al, Blood, 2019) where a greater increase in cytokine levels and risk for CRS is seen with high intensity LDC. These data highlight how standard BSA-based Flu dosing results in significant PK variability and overestimates Flu AUC, increasing the risk of CAR-T toxicities. Prospective validation of our model-based findings through measurement of Flu blood levels, CAR-T PK, and clinical outcomes is warranted.

The cycle effect quantified: reduced tumour uptake in subsequent cycles of [177Lu]Lu-HA-DOTATATE during peptide receptor radionuclide therapy.

Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [177Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach. A population PK model was developed using imaging data from 48 patients who received multiple cycles of [177Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle. The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one. Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.

Population pharmacokinetics of apixaban in a real-life hospitalized population from the OptimAT study.

This study aimed to characterize apixaban pharmacokinetics (PKs) and its variability in a real-world clinical setting of hospitalized patients using a population PK (PopPK) approach. Model-based simulations helped to identify factors that affect apixaban exposure and their clinical significance. A classic stepwise strategy was applied to determine the best PopPK model for describing typical apixaban PKs in hospitalized patients from the OptimAT study (n = 100) and evaluating the associated variability and influencing factors. Apixaban exposure under specific conditions was assessed using the final model. A two-compartment model with first-order absorption and elimination best described the data. The developed PopPK model revealed a major role of renal function and a minor role of P-glycoprotein phenotypic (P-gp) activity in explaining apixaban variability. The final model indicated that a patient with stage 4 chronic kidney disease (creatinine clearance [CLcr] = 15-29 mL/min) would have a 45% higher drug exposure than a patient with normal renal function (CLcr >90 mL/min), with a further 12% increase if the patient was also a poor metabolizer of P-gp. A high interindividual variability in apixaban PKs was observed in a real-life setting, which was partially explained by renal function and by P-gp phenotypic activity. Target apixaban concentrations are reached under standard dosage regimens, but overexposure can rapidly occur in the presence of cumulative factors warranting the development of a predictive tool for tailoring apixaban exposure and its clinical utility in at-risk patients.

­Pharmacokinetics of antimalarial drugs used to treat uncomplicated malaria in breastfeeding mother-infant pairs: An observational pharmacokinetic study

Background: Data surrounding the exposure of the breastfed infant to drugs and any associated risks are sparse. Drugs usually are transferred to milk in small quantities, and many have been used without obviously noticeable infant toxicity for many years – this lack of a ‘safety signal’ has further reduced the interest in studying mother-to-infant transfer of the drugs. In sub-Saharan Africa, pregnant women are at risk of Plasmodium falciparum infection, and one in four women have evidence of placental infection at the time of delivery. Artemisinin-based combination therapies (ACTs), primarily artemether-lumefantrine (AL), are the current first-line treatment for uncomplicated Plasmodium falciparum malaria, with the same dosing recommendations in breastfeeding women as those in the adult population. Dihydroartemisinin-piperaquine (DP) is routinely used as an alternative to AL in Uganda. However, lactation pharmacokinetics (PK) of ACTs are unknown. Pharmacokinetic characterization of anti-malarial transfer to breast milk and breastfed infants is crucial in understanding the potential consequences to the infant, in terms of therapeutic- and prophylactic effects as well as potential toxicity. Methods: This observational study will enroll 30 mother-infant pairs, and aims to characterize the breastmilk transfer of antimalarial medications (AL and DP) to infants when these ACTs are administered to mothers as part of treatment for uncomplicated malaria. In addition, we will assess the mental health of the breastfeeding mothers enrolled as well as the well-being of their children. PK samples of maternal blood, breastmilk and breastfeeding infant’s blood will be obtained at specific times points. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Conclusions: We anticipate that findings from this research will guide to develop a PK model describing lumefantrine and piperaquine disposition and will provide a framework to foster other lactation pharmacokinetic studies in different disease areas.

Population Pharmacokinetic Modeling and Determination of Individual Exposure to Avalglucosidase Alfa in Adolescent and Adult Patients With Late-Onset Pompe Disease: Analysis of Pooled Data From Phase I to III Clinical Trials.

Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach. The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software. Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions. A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability.

Extended Use of Levonorgestrel-Releasing Intrauterine System (LNG-IUS) 52 mg: A Population Pharmacokinetic Approach to Estimate In Vivo Levonorgestrel Release Rates and Systemic Exposure Including Comparison With Two Other LNG-IUSs

ABSTRACT With over 30 years of use, levonorgestrel-releasing intrauterine systems (LNG-IUSs) have proven to be highly effective methods of contraceptives. The active ingredient in LNG-IUS, levonorgestrel (LNG), is released directly into the uterine cavity, which causes suppression of endometrial maturation and thickened cervical mucus. A variety of LNG-IUS options exhibit well-established safety profiles and efficacy, providing anywhere between 2 and 18 times lower systemic exposure when compared with LNG-containing pills or implants. Patient-centered decision-making regarding product choice may be encouraged through standardized comparisons of LNG release and exposure during the time of their respective usage periods. Evaluation of the efficacy, safety, and PK of extended Mirena use from beyond 5 years to the conclusion of 8 years was designed in the Mirena Extension Trial (MET), thereby facilitating comparisons with LNG-IUS 19.5 mg and LNG-IUS 13.5 mg. Using validated liquid chromatography-tandem mass spectrometry methods and SHBG concentrations, the authors determined concentrations of plasma LNG levels. Dichloromethane was used for extracting residual LNG from the elastomer material from removed IUS devices, which was then quantified via liquid chromatography and external calibration on a reversed-phase column. Although previous models used measured LNG and SHBG (serum) concentrations, the population pharmacokinetics (popPK) allows for a uniform method of comparison among different pharmacologic studies. The popPK approach allows for a reliable estimates of in vivo LNG exposure and release during the entirety of the 8-year use period. The MET enrolled premenopausal women aged 18–35 years for a multicenter, single-arm study regarding patients who had used LNG-IUS 52 mg for the last 4.5–5 years for up to 8 years. The study took place from December 22, 2016 to May 28, 2021 throughout 54 US centers, with the primary outcome of contraceptive efficacy and failure rate. Participants each provided written, informed consent. Study strengths of the popPK approach included its robust methodology, its ability to provide in vivo release rate estimates, a stepwise demo of model suitability from use years 6 to 8, model-based estimation of unbound LNG, and the ability to provide estimates for both population and individual PK profiles from sparse available sampling. Limitations include the possibility of findings being group effects possibly inapplicable to all LNG-IUS users. In addition, the data fail to provide local endometrial and cervical LNG concentrations due to the systemic nature of the LNG exposure. Finally, the popPK Mondale should not be used for theoretical question addressing (such as creating rate release estimates outside of available data sets). In conclusion, a broad data set indicates that reliable LNG exposure is delivered by 8-year popPK and release models for up to 7 years of LNG-IUs 52 mg use. Efficacy is data-supported for 6–8 years of use, with constant LNG release throughout this time frame. Systemic LNG exposure from LNG-IUD 52 mg proved both comparable to other LNG-IUS devices and significantly lower than oral and implanted LNG-containing contraceptives.

Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy.

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.

Pharmacokinetics of drugs used to treat drug sensitive-tuberculosis in breastfeeding mother-infant pairs: An observational pharmacokinetic study

Background Globally, more than half of women take medicines whilst breastfeeding. Data concerning the exposure of the breastfed infant to drugs and any related risks are sparce. Lactation studies are only rarely performed close to licensing for medicines anticipated to be widely used in women of childbearing age. Medicines taken by breastfeeding mothers on tuberculosis (TB) treatment can be transferred to the breastfed infant. Potential effects of anti-tuberculosis medicines on nursing infants are not well understood. Potential risks are the development of adverse drug effects in the breastfed infant and selection for resistance, whereas potential benefits might include exposure to potentially prophylactic concentrations of the drug. Pharmacokinetic studies are therefore necessary to understand this situation fully. Methods This study will enroll 20 mothers receiving first-line anti-tuberculosis medicines, together with their breastfed infants, with the aim of characterizing the breastmilk transfer of the medicines from the mother to the infants. Samples of maternal blood, breastmilk and breastfeeding infant’s blood will be obtained at specific time points for bioanalysis of drug concentrations. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Additionally, the study will assess the psychological status of breastfeeding women and the well-being of their infants. Maternal depression is linked to long-term negative consequences for the infant’s physiological regulation, poor growth-promoting setting for the infants, and inappropriate interactive conduct, characterized by low compassion, constrained range of emotional expression, and varying provision of the infant’s budding engagement. Conclusions This study will provide the first systematic characterization of mother-to-infant transfer of first-line anti-tuberculosis medicines through breast milk. A mathematical pharmacokinetics model characterizing plasma-to-breastmilk transfer of rifampicin, isoniazid, ethambutol, and pyrazinamide will be developed and used to characterize infant exposure through breast milk. Our findings will contribute towards treatment optimization in breastfeeding and provide a framework to foster other lactation pharmacokinetic studies.