Pharmacokinetic Variability Research Articles

Disulfiram: Mechanisms, Applications, and Challenges.

Background: Since disulfiram's discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were "disulfiram" and "Antabuse". Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948-2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a "repurposed" agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.

Tigecycline Immunodetection Using Developed Group-Specific and Selective Antibodies for Drug Monitoring Purposes.

Tigecycline (TGC), a third-generation tetracycline, is characterized by a more potent and broad antibacterial activity, and the ability to overcome different mechanisms of tetracycline resistance. TGC has proven to be of value in treatment of multidrug-resistant infections, but therapy can be complicated by multiple dangerous side effects, including direct drug toxicity. Given that, a TGC immunodetection method has been developed for therapeutic drug monitoring to improve the safety and efficacy of therapy. The developed indirect competitive ELISA utilized TGC selective antibodies and group-specific antibodies interacting with selected coating TGC conjugates. Both assay systems showed high sensitivity (IC50) of 0.23 and 1.59 ng/mL, and LOD of 0.02 and 0.05 ng/mL, respectively. Satisfactory TGC recovery from the spiked blood serum of healthy volunteers was obtained in both assays and laid in the range of 81-102%. TGC concentrations measured in sera from COVID-19 patients with secondary bacterial infections were mutually confirmed by ELISA based on the other antibody-antigen interaction and showed good agreement (R2 = 0.966). A TGC pharmacokinetic (PK) study conducted in three critically ill patients proved the suitability of the test to analyze the therapeutic concentrations of TGC. Significant inter-individual PK variability revealed in this limited group supports therapeutic monitoring of TGC in individual patients and application of the test for population pharmacokinetic modelling.

Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.

There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.

Current Understanding of Inherited Modifiers of FVIII Pharmacokinetic Variation.

The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including VWF gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Critically Ill Patients with Renal Hyperfiltration: Optimizing Antibiotic Dose.

Renal hyperfiltration (RHF) is a prevalent phenomenon in critically ill patients characterized by augmented renal clearance (ARC) and increased of elimination of renally eliminated medications. Multiple risk factors had been described and potential mechanisms may contribute to the occurrence of this condition. RHF and ARC are associated with the risk of suboptimal exposure to antibiotics increasing the risk of treatment failure and unfavorable patient outcomes. The current review discusses the available evidence related to the RHF phenomenon, including definition, epidemiology, risk factors, pathophysiology, pharmacokinetic variability, and considerations for optimizing the dosage of antibiotics in critically ill patients.

Population Pharmacokinetics and Dosing Simulations of Ampicillin and Sulbactam in Hospitalised Adult Patients.

The pharmacokinetic variability of ampicillin-sulbactam in adults has not been extensively described, particularly in patients with a reduced renal function (i.e., <60mL/min). This study investigated the population pharmacokinetics of ampicillin and sulbactam in patients with a wide range of renal functions and sought to define dosing approaches that have a high likelihood for optimising drug exposure. Serial blood samples were collected from 16 adult patients receiving intravenous ampicillin-sulbactam in general wards. Total ampicillin and sulbactam concentrations were measured by chromatographic assay and pharmacokinetic parameters were estimated using Pmetrics®. Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) of free ampicillin and sulbactam concentrations exceeding the minimum inhibitory concentration (MIC) for 60% and 100% of the dosing interval. Fractional target attainment (FTA) was calculated against MIC distributions of common hospital pathogens. A threshold of ≥90% and ≥95% was used to define both optimal PTA and FTA, respectively. The median (range) age, weight, and serum creatinine of the study population was 68 (40-82) years, 62 (40-82) kg, and 1.4 (0.6-6.4) mg/dL, respectively. The pharmacokinetics of ampicillin and sulbactam were best described by a two-compartment model with serum creatinine most closely associated with clearance for both drugs. The estimated ampicillin and sulbactam clearances were 5.58 L/h and 4.79 L/h, respectively, while the volumes of distribution were 12.6L and 15.36L, respectively. Approved dosing regimens of ampicillin-sulbactam were sufficient against MICs≤8 and ≤4 mg/L, respectively. A 4-h infusion enabled optimal PTA at higher MICs. For both dosing targets, optimal FTAs were obtained against Streptococcus pneumoniae. Optimal FTAs were obtained against the susceptible MIC distributions of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Applying a 4-h infusion will enhance PTA and FTA, particularly at higher MICs.

Exposure toxicity and response relationship of cabozantinib (CABO) in patients with metastatic renal cell carcinoma (mRCC).

676 Background: At the recommended dose of 60mg/day in mRCC, CABO is associated with frequent and/or severe toxicities in mRCC, which may be modified, along with clinical benefit, by interindividual variability in pharmacokinetics (PK). The objective of this multicentre ambispective study was to determine whether the PK of CABO could help to better predict efficacy and early dose-limiting toxicities (DLT) in mRCC. Methods: We collected plasma and determined the concentration of CABO in the first 3 months of initiation in all consecutive mRCC patients (pts) treated in 3 French oncology departments from Dec. 2016 to Mar. 2022. Correlation of plasma trough concentration (Cmin) with objective response rate (ORR), progression free survival (PFS), overall survival (OS), and DLT (any discontinuation or dose reduction in the first 3 months) was explored. An optimal therapeutic range was defined using ROC curves to predict efficacy and DLT. Cox proportional-hazards models were used to identify risk factors of DLT, progression and death. Results: 80 pts were included, 80% clear cell RCC, mean age 62.1 years (+/-13.3) and sex ratio (male/female) 3.2. CABO was administered as second-line, or third-or later-line in 36% and 55% of pts, respectively. Thirty-six (45 %) and 32 (40%) pts initiated CABO at 60mg and 40mg, respectively. After a median follow-up of 17.9 months (9.4-27.9), 24 (30%) were alive, 16 (20%) were still on CABO, and 46 (50%) had experienced DLT with a median to onset of 2 months (CI95%: 0.7-6.2). In the whole cohort, median Cmin was 614 ng/mL [IQR 439-827], with an interindividual variability in dose-normalized exposure of 47.5%. DLT was not associated with the starting dose (p=0.18) but was associated with higher baseline albumin (p=0.03) and higher Cmin (p=0.003). In multivariate analysis, only Cmin was associated with DLT (HR per 100-unit increase: 1.35 [1.03-1.77]; p=0.03). ORR was achieved in 25/79 (32%) evaluable pts, including 16/35 (46%) pts starting CABO at 60mg vs 9/44 (20%) in pts starting at 20/40mg (p=0.03). No difference was found in PFS and OS according to the starting dose (p=0.72 and p=0.49, respectively), nor with previously reported Cmin≥750ng/mL (vs &lt;750, p=0.77 for PFS and p=0.59 for OS). According to the ROC curves, Cmin&lt;350ng/mL tended to be associated with shorter PFS (p=0.0748) and OS (p=0.264), and that Cmin&gt;800ng/mL was significantly associated with DLT (HR 1.56 [1.13-2.15]; p=0.009), although it was not associated with an increase in PFS (p=0.94) or OS (p=0.33). Conclusions: We show that Cmin of CABO is more robustly associated with DLT and PFS/OS than the starting dose, probably due to a high interindividual variability in exposure. Early plasma drug monitoring associated with a target Cmin of 350-800 ng/mL may be useful to optimize CABO in mRCC pts. Future studies should focus on validating this therapeutic range in external validation cohorts.

Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of Mirogabalin in Healthy Chinese Participants: A Randomized, Double-Blind, Placebo-Controlled Study.

Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants. In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45years were randomly allocated to receive single- (5, 10, or 15mg, daily) or multiple-dose (5mg titrated to 15mg, twice-daily, over 22days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis. Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00h) and eliminated (mean terminal elimination half-life, 2.57-3.08h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant. Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15mg twice-daily.

Population pharmacokinetic dosimetry model using imaging data to assess variability in pharmacokinetics of 177 Lu-PSMA-617 in prostate cancer patients.

Studies to evaluate and optimize [177 Lu]Lu-PSMA treatment focus primarily on individual patient data. A population pharmacokinetic (PK) dosimetry model was developed to explore the potential of using imaging data as input for population PK models and to characterize variability in organ and tumor uptake of [177 Lu]Lu-PSMA-617 in patients with low volume metastatic prostate cancer. Simulations were performed to identify the effect of dose adjustments on absorbed doses in salivary glands and tumors. A six-compartment population PK model was developed, consisting of blood, salivary gland, kidneys, liver, tumor, and a lumped compartment representing other tissue (compartment 1-6, respectively), based on data from 10 patients who received [177 Lu]Lu-PSMA-617 (2 cycles, ~ 3 and ~ 6GBq). Data consisted of radioactivity levels (decay corrected) in blood and tissues (9 blood samples and 5 single photon emission computed tomography/computed tomography scans). Observations in all compartments were adequately captured by individual model predictions. Uptake into salivary glands was saturable with an estimated maximum binding capacity (Bmax ) of 40.4MBq (relative standard error 12.3%) with interindividual variability (IIV) of 59.3% (percent coefficient of variation [CV%]). IIV on other PK parameters was relatively minor. Tumor volume was included as a structural effect on the tumor uptake rate constant (k15 ), where a two-fold increase in tumor volume resulted in a 1.63-fold increase in k15 . In addition, interoccasion variability on k15 improved the model fit (43.5% [CV%]). Simulations showed a reduced absorbed dose per unit administered activity for salivary glands after increasing radioactivity dosing from 3 to 6GBq (0.685 Gy/GBq vs. 0.421 Gy/GBq, respectively). All in all, population PK modeling could help to improve future radioligand therapy research.

External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia.

Methotrexate (MTX) is a key immunosuppressant for children with acute lymphoid leukemia (ALL), and it has a narrow therapeutic window and relatively high pharmacokinetic variability. Several population pharmacokinetic (PopPK) models of MTX in ALL children have been reported, but the validity of these models for model-informed precision dosing in clinical practice is unclear. This study set out to evaluate the predictive performance of published pediatric PopPK models of MTX using an independent patient cohort. A PubMed literature search was performed to identify suitable models for evaluation. Demographics and measurements of the validation dataset were retrospectively collected from the medical records of ALL children who had received intravenous MTX. Predictive performance for each model was assessed by visual comparison of predictions to observations, median and mean predicted error (PE), and relative root mean squared error (RMSE). Six models were identified for external evaluation, carried out on a dataset containing 354 concentrations from 51 pediatrics. Model performance varied considerably from one model to another. Different models had the median PE for population and individual predictions at -33.23% to 442.04% and -25.20% to 6.52%, mean PE for population and individual predictions at -25.51% to 780.87% and 1.33% to 64.44%, and RMSE for population and individual predictions at 62.88% to 1182.24% and 63.39% to 152.25%. All models showed relatively high RMSE. Some of the published models showed reasonably low levels of bias but had some problems with imprecision, and extensive evaluation is needed before model application in clinical practice.

Interplay of Breast Cancer Resistance Protein (Bcrp/Abcg2), Sex, and Fed State in Oral Pharmacokinetic Variability of Furosemide in Rats

Poor and variable oral bioavailability of furosemide (FUR) presents critical challenges in pharmacotherapy. We investigated the interplay of breast cancer resistance protein (Bcrp)-mediated transport, sex, and fed state on FUR pharmacokinetics (PK) in rats. A crossover PK study of FUR (5 mg/kg, oral) was performed in Sprague-Dawley rats (3 males and 3 females), alone or with a Bcrp inhibitor, novobiocin (NOV) (20 mg/kg, oral), in both fed and fasted states. Co-administration of NOV significantly increased FUR extent (AUC) and rate (Cmax) of exposure by more than two-fold, which indicates efficient Bcrp inhibition in the intestine. The female rats showed two-fold higher AUC and Cmax, and two-fold lower renal clearance of FUR compared to the male rats. The latter was correlated with higher renal abundance of Bcrp and organic anion transporters (Oats) in the male rats compared to age-matched female rats. These findings suggest that the PK of Bcrp and/or Oat substrates could be sex-dependent in rats. Moreover, allometric scaling of rat PK and toxicological data of Bcrp substrates should consider species and sex differences in Bcrp and Oat abundance in the kidney. Considering that Bcrp is abundant in the intestine of rats and humans, a prospective clinical study is warranted to evaluate the effect of Bcrp inhibition on FUR PK. The potential confounding effect of the Bcrp transporter should be considered when FUR is used as a clinical probe of renal organic anion transporter-mediated drug-drug interactions. Unlike human data, no food-effect was observed on FUR PK in rats.

Contribution of voriconazole N-oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection.

Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. Based on 225 measurements, the median and interquartile range were 2.4μg/ml (1.2; 4.2), 2.1μg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2μg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2μg/ml and above 5.5μg/ml, respectively, at the next visit. Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.

Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine.

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent.

Interchangeability of generic drugs for subpopulations: Bioequivalence simulation from a nonparametric PK model of gabapentin generic drugs.

We aim to identify pathophysiological pharmacokinetic subpopulations for whom there is a difference in comparative bioavailability compared to a healthy population. We used simulated exposures from a nonparametric model of multiple generics and the originator gabapentin. Exposure was simulated for virtual populations with pharmacokinetic characteristics beyond those of healthy subjects with regard to rate of absorption, volume of distribution and reduced renal function. Virtual parallel design bioequivalence studies were performed using a random sample of 24 simulated subjects, with standard acceptance criteria. Results indicated increased pharmacokinetic variability for patient populations with a lower rate of absorption or a reduced renal function, but no change in the average comparable bioavailability ratio. This increased variability results in a reduced likelihood of demonstrating bioequivalence. Observations were similar for comparisons between all different formulations, as well as between subjects who received the identical formulation in a repeated fashion. No relevant effect was observed for simulations with increased volume of distribution. Our simulations indicate that the reduced likelihood of demonstrating bioequivalence for subjects with altered pharmacokinetics is not influenced by a formulation switch, nor does the average comparable bioavailability ratio change, therefore these results support generic interchangeability and current approval requirements for generics.

Simultaneous quantification of venetoclax and voriconazole in human plasma by UHPLC-MS/MS and its application in acute myeloid leukemia patients

Venetoclax, an orally bioavailable BCL‐2 inhibitor, has been regarded as a breakthrough for the treatment of leukemia but has a wide interindividual variability and drug-drug interaction in pharmacokinetics. In this study, a simple and sensitive ultra-high performance liquid chromatography-tandem with mass spectrometry method was established and fully validated to quantify venetoclax and voriconazole simultaneously in human plasma. After protein precipitation, the analytes were separated on a Hypersil GOLD C18 column (3 µm, 2.1 × 50 mm) by gradient elution. The mass detection was operated under multiple reaction monitoring mode at m/z 868.5 →636.2 for venetoclax, 350.0 → 127.0 for voriconazole and 353.0 → 127.0 for voriconazole-D3(Internal Standard). The calibration ranges were 0.1–10 μg/mL for venetoclax and 0.05–10 μg/mL for voriconazole with correlation coefficients (r2)＞0.998. The validated method was successfully applied to the pharmacokinetic study in acute myeloid leukemia patients receiving venetoclax with or without voriconazole. The results suggested that co-treatment with 200 mg q12h voriconazole, the peak concentration of venetoclax (100 mg qd) could be raised to the same level as the 400 mg qd group. However, the trough concentration of venetoclax (100 mg qd) was much higher than that of the 400 mg qd group. Therapeutic drug monitoring might give some guidance for the adjustment of dosing regimens to guarantee the drug efficacy and safety of patients to some extent.

Pharmacokinetic Alterations Associated with Critical Illness.

Haemodynamic, metabolic, and biochemical derangements in critically ill patients affect drug pharmacokinetics and pharmacodynamics making dose optimisation particularly challenging. Appropriate therapeutic dosing depends on the knowledge of the physiologic changes caused by the patient's comorbidities, underlying disease, resuscitation strategies, and polypharmacy. Critical illness will result in altered drug protein binding, ionisation, and volume of distribution; it will also decrease oral drug absorption, intestinal and hepatic metabolism, and renal clearance. In contrast, the resuscitation strategies and the use of vasoactive drugs may oppose these effects by leading to a hyperdynamic state that will increase blood flow towards the major organs including the brain, heart, kidneys, and liver, with the subsequent increase of drug hepatic metabolism and renal excretion. Metabolism is the main mechanism for drug clearance and is one of the main pharmacokinetic processes affected; it is influenced by patient-specific factors, such as comorbidities and genetics; therapeutic-specific factors, including drug characteristics and interactions; and disease-specific factors, like organ dysfunction. Moreover, organ support such as mechanical ventilation, renal replacement therapy, and extracorporeal membrane oxygenation may contribute to both inter- and intra-patient variability of drug pharmacokinetics. The combination of these competing factors makes it difficult to predict drug response in critically ill patients. Pharmacotherapy targeted to therapeutic goals and therapeutic drug monitoring is currently the best option for the safe care of the critically ill. The aim of this paper is to review the alterations in drug pharmacokinetics associated with critical illness and to summarise the available evidence.

356 - Children Under 2 Years Old Treated with Ruxolitinib for Acute and Chronic Graft-Versus-Host-Disease Demonstrate Variable Pharmacokinetics

356 - Children Under 2 Years Old Treated with Ruxolitinib for Acute and Chronic Graft-Versus-Host-Disease Demonstrate Variable Pharmacokinetics

The potential and pitfalls of artificial intelligence in clinical pharmacology.

Artificial intelligence (AI) involves using data and algorithms to perform activities normally achieved through human intelligence. AI and its key component machine learning contextualize data and enhance decision making to transform how we operate, discover, and develop drugs. Transforming clinical pharmacology (CP) as AI-augmented CP (AI/CP) requires an ecosystem including digitized data collection, standardized processes, complementary technologies, and an ethical framework. This commentary aims to highlight the future perspectives of AI/CP in drug development.

Population Pharmacokinetic Modeling of Zaltoprofen in Healthy Adults: Exploring the Dosage Regimen.

Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications.