Pharmacokinetics Of Metabolites Research Articles

Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain.

Simple SummaryPatients with moderate to severe cancer-related pain are frequently treated with oxycodone, a strong-acting opioid. However, treatment with oxycodone does not always lead to sufficient analgesic action. In order to determine which factors affect treatment outcomes, we performed an observational study and developed a population pharmacokinetic model. The model described oxycodone, nor-oxycodone and nor-oxymorphone pharmacokinetics. The association between oxycodone or oxycodone metabolites’ exposure with pain scores and adverse events was not significant. The combined oxycodone, nor-oxycodone and nor-oxymorphone model is a good starting point for further unravelling the factors that affect the pharmacokinetic/pharmacodynamic relation of oxycodone and its metabolites.Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.

Pharmacokinetic Characteristics, Tissue Bioaccumulation and Toxicity Profiles of Oral Arsenic Trioxide in Rats: Implications for the Treatment and Risk Assessment of Acute Promyelocytic Leukemia.

Oral arsenic trioxide (ATO) has demonstrated a favorable clinical efficiency in the treatment of acute promyelocytic leukemia (APL). However, the pharmacokinetic characteristics, tissue bioaccumulation, and toxicity profiles of arsenic metabolites in vivo following oral administration of ATO have not yet been characterized. The present study uses high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) to assess the pharmacokinetics of arsenic metabolites in rat plasma after oral and intravenous administration of 1 mg kg−1 ATO. In addition, the bioaccumulation of arsenic metabolites in blood and selected tissues were evaluated after 28 days oral administration of ATO in rats at a dose of 0, 2, 8, and 20 mg kg−1 d−1. The HPLC-HG-AFS analysis was complemented by a biochemical, hematological, and histopathological evaluation conducted upon completion of ATO treatment. Pharmacokinetic results showed that arsenite (AsIII) reached a maximum plasma concentration rapidly after initial dosing, and the absolute bioavailability of AsIII was 81.03%. Toxicological results showed that the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and white blood cells (WBC) in the 20 mg kg−1 d−1 ATO group were significantly increased compared to the control group (p < 0.05). The distribution trend of total arsenic in the rat was as follows: whole blood > kidney > liver > heart. Dimethylated arsenic (DMA) was the predominant bioaccumulative metabolite in the whole blood, liver, and heart, while monomethylated arsenic (MMA) was the predominant one in the kidney. Collectively, these results revealed that oral ATO was rapidly absorbed, well-tolerated, and showed organ-specific and dose-specific bioaccumulation of arsenic metabolites. The present study provides preliminary evidence for clinical applications and the long-term safety evaluation of oral ATO in the treatment of APL.

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Evaluation of Lidocaine and Metabolite Pharmacokinetics in Hyaluronic Acid Injection.

Lidocaine-incorporated hyaluronic acid injection (LHA) is considered a promising way to increase patient compliance. Various reviews and analyses have been conducted to verify that the addition of lidocaine had no effect on the product quality of hyaluronic acid injections. However, possible pharmacokinetic (PK) alterations of lidocaine and its active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX), in hyaluronic acid injection have not been studied so far. Thus, the objective of this study was to evaluate lidocaine and its metabolite PK after 0.3% lidocaine solution or LHA injection and to investigate any changes in PK profiles of lidocaine and its active metabolites. To do this, a novel bio-analytical method for simultaneous determination of lidocaine, MEGX, and GX in rat plasma was developed and validated. Then, plasma concentrations of lidocaine and its active metabolites MEGX and GX following subcutaneous (SC) injection of 0.3% lidocaine solution or LHA with 0.3–1% lidocaine in male Sprague-Dawley rats were successfully determined. The obtained data were used to develop a parent-metabolite pharmacokinetic (PK) model for LHA injection. The half-life, dose-normalized Cmax, and AUCinf of lidocaine after SC injection of lidocaine solution and LHA did not show statistically significant difference. The PK characteristics of lidocaine after LHA administration were best captured using a two-compartment model with combined first-order and transit absorption and its clearance described with Michaelis–Menten and first-order elimination kinetics. Two one-compartment models were consecutively added to the parent model for the metabolites. In conclusion, the incorporation of lidocaine in hyaluronic acid filler injection did not alter the chemical’s pharmacokinetic characteristics.

Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes

The approved drug thalidomide is teratogenic in humans, nonhuman primates, and rabbits but not in rodents. The extensive biotransformation of 5'-hydroxythalidomide after oral administration of thalidomide (250 mg/kg) in rats was investigated in detail using liquid chromatography-tandem mass spectrometry. Probable metabolites 5'-hydroxythalidomide sulfate and glucuronide were extensively formed, with approximately tenfold and onefold peak areas, respectively, to the primary 5'-hydroxythalidomide measured using authentic standards. As a minor metabolite, 5-hydroxythalidomide was also detected. The output of simplified physiologically based pharmacokinetic rat models was consistent with the observed in vivo data under a metabolic ratio of 0.05 for the hepatic intrinsic clearance of thalidomide to unconjugated 5'-hydroxythalidomide. The aggregate of unconjugated and sulfate/glucuronide conjugated 5'-hydroxythalidomide forms appear to be the predominant metabolites in rats. Two hours after oral administration of thalidomide (100 mg/kg) to chimeric mice humanized with four different batches of genotyped human hepatocytes, the plasma concentration ratios of 5-hydroxythalidomide to 5'-hydroxythalidomide were correlated with replacement indexes of human liver cells previously transplanted in immunodeficient mice. These results indicate that rodent livers mediate thalidomide primary oxidation, leading to extensive deactivation in vivo to unconjugated/conjugated 5'-hydroxythalidomide and suggest that thalidomide activation might be dependent on the humanized livers in mice transplanted with human hepatocytes.

Pharmacokinetics of Enteric-Coated Mycophenolate Sodium Metabolites in Patients Over 60 Years Old Within the First Year After Renal Transplantation

ObjectiveIt is still unclear whether mycophenolic acid (MPA) doses should be adjusted for older patients. Therefore, we compared the pharmacokinetics of MPA, mycophenolic acid glucuronide (MPAG), and free MPA (fMPA) between older and younger renal transplant recipients. MethodsWe included 12 patients <60 years and 6 patients >60 years within the first year after renal transplantation, who were receiving enteric-coated mycophenolate sodium, tacrolimus, and steroids. Blood samples were collected up to 12 hours after drug administration. ResultsMPA and fMPA pharmacokinetics were similar for patients <60 and >60 years; however, the MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) was 1.2-fold lower in the older patients. MPAG pharmacokinetics were more than 1.5-fold higher in patients >60 years, which might be related to deteriorated renal function in older people. Moreover, the mean (MPAG AUC0-12)/(MPA AUC0-12) ratio was more than 2-fold higher in patients >60 years. The second maximal MPA concentration was more frequently observed in patients <60 years, although all patients received tacrolimus. The percentage of patients with MPA concentration before the next drug dose (Ctrough) and AUC0-12 within and below target was the same in both groups. All patients >60 years had MPA AUC0-12 >30 μg·h/mL within 22 to 114 days after transplantation. ConclusionsMPA therapeutic monitoring should be recommended in enteric-coated mycophenolate sodium--treated patients >60 years because MPA AUC0-12 exceeded the recommended value in half of the studied patients.

Plasma pharmacokinetics of (poly)phenol metabolites and catabolites after ingestion of orange juice by endurance trained men

The health benefits of orange juice (OJ) consumption are attributed in part to the circulating flavanone phase II metabolites and their microbial-derived ring fission phenolic catabolites. The present study investigated these compounds in the bloodstream after acute intake of 500 mL of OJ. Plasma samples obtained at 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h after OJ intake were analysed by HPLC-HR-MS. Eleven flavanone metabolites and 36 phenolic catabolites were identified and quantified in plasma. The main metabolites were hesperetin-3′-sulfate with a peak plasma concentration (Cmax) of 80 nmol/L, followed by hesperetin-7-glucuronide (Cmax 24 nmol/L), hesperetin-3′-glucuronide (Cmax 18 nmol/L) and naringenin-7-glucuronide (Cmax 21 nmol/L). Among the main phenolic catabolites to increase in plasma after OJ consumption were 3′-methoxycinnamic acid-4′-sulfate (Cmax 19 nmol/L), 3-hydroxy-3-(3′-hydroxy-4′-methoxyphenyl)propanoic acid (Cmax 20 nmol/L), 3-(3′-hydroxy-4′-methoxyphenyl)propanoic acid (Cmax 19 nmol/L), 3-(4′-hydroxyphenyl)propanoic acid (Cmax 25 nmol/L), and 3-(phenyl)propanoic acid (Cmax 19 nmol/L), as well as substantial amounts of phenylacetic and hippuric acids. The comprehensive plasma pharmacokinetic profiles that were obtained are of value to the design of future ex vivo cell studies, aimed at elucidating the mechanisms underlying the potential health benefits of OJ consumption. Clinical trial registration numberThis trial was registered at clinicaltrials.gov as NCT02627547.

Single-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites Alone and in Combination with Gemfibrozil, Itraconazole, or Rifampin in Healthy Subjects: A Randomized, Parallel-Group, Open-Label Study.

The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. This was a phase1, randomized, parallel-group, open-label study with two parts. In part1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46mg (groupA, n = 20) or oral doses of gemfibrozil 600mg twice daily for 17days with a single oral dose of ozanimod 0.46mg on day4 (groupB, n = 20). In part2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92mg (groupC, n = 20), oral doses of itraconazole 200mg once daily for 17days with a single oral dose of ozanimod 0.92mg on day4 (groupD, n = 20), or oral doses of rifampin 600mg once daily for 21days with a single oral dose of ozanimod 0.92mg on day8 (groupE, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20-22h while the mean t1/2 for CC112273 and CC1084037 were approximately 10days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. Clinical trial: NCT03624959.

Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis

BackgroundRecent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers. MethodsThree increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time–plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach. ResultsThe pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics. ConclusionsThe model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. Clinical trial registrationDutch Cochrane Center 5359.

Abstract CT168: Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations

Abstract AZD4635 is an orally administered, selective adenosine 2A receptor (A2AR) antagonist, being evaluated in patients with advanced solid tumors. In the phase 1 trial, safety and pharmacokinetics (PK) of AZD4635 nanosuspension (NS) was assessed as monotherapy or in combination with durvalumab. In the HV study, a single dose of AZD4635 was evaluated to assess relative bioavailability, effect of high fat meal and effect of proton pump inhibitor (PPI) on new capsule formulation (CF). Here we present PK results from both trials to provide dosing and formulation recommendation for ongoing clinical trials. Methods: Phase 1 Study in CP: An open-label, multicenter study in advanced solid malignancies (121 patients PK evaluable), AZD4635 was administered as a NS at various dose levels (125 mg BID, 75mg QD, 100 mg QD) as monotherapy or in combination (75 or 100 mg QD) with durvalumab (NCT02740985). The PK parameters of AZD4635 and its metabolites have been characterized in patients after single and multiple doses. Phase 1 Study in HV: An open-label, single-dose (50 mg), 2-part crossover clinical pharmacology study was conducted in 20 HV (non-smoking, male) (NCT03710434). Part A was a 2-period randomized crossover study of AZD4635 as NS or CF. Part B was a fixed-sequence crossover study to evaluate effect of high fat meal and co-administration of PPI (lansoprazole) on AZD4635 CF. PK and safety assessments were obtained for up to 120 h post-dose in each treatment period, and the treatments were separated with at least a 9-day washout period. Results: AZD4635 NS rapidly appeared in plasma after single or multiple oral administration with tmax of 1 h and Cmax were 594.13, 580.21, and 770.66 ng/mL and AUC were 4780.3, 4364.8, and 5972.89 ng•hr/mL at 75, 100 and 125 mg, respectively with a mean t1/2 of 13.1 - 18.1 h following a single-dose administration. There was minimal accumulation at steady state with high inter-individual variability (43 - 114%). Metabolites PK will be presented. In HV, administration of CF resulted in absorption rates similar to NS with tmax of 1.5 h and had 27% and 10% higher Cmax and AUC, respectively compared to NS. Administering AZD4635 CF after a high fat meal resulted in 56% and 12% decrease in Cmax and AUC, respectively compared to the fasted state. In the presence of PPI (lansoprazole), peak and overall exposures (Cmax, AUC and tmax) were similar to those for CF administered alone. Conclusion: Based on totality of exposure and safety data from ongoing Phase I study in CP at various doses of AZD4635 NS, and data from HV study for both NS and CF, a dose of 75 mg CF is proposed RP2D for further clinical studies. As food can mitigate gastrointestinal toxicities, and there was a lack of significant effect on AUC, the current fasting restrictions have been relaxed to allow patients to receive AZD4635 with or without food. No impact of PPI allows for better compliance as the target patient population may also be receiving gastric modifiers. Citation Format: Ganesh Moorthy, Gayle Pageau Pouliot, Lorraine Graham, Chris Wilks, Tinnu Sarvotham, Patrick Mitchell, Lindsey Jung, Yan Li, Wenlin Shao, Ganesh Mugundu. Clinical pharmacology of AZD4635 (A2ARi): Integration of PK data from cancer patients (CP) and healthy volunteer (HV) clinical trials to provide dosing recommendations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT168.

Abstract 321: Novel bone microenvironment model of prostate cancer with chitosan fiber matrix and osteoblast in 3D culture

Abstract BACKGROUND: The interaction between prostate cancer cells and osteoblast is essential for the development of bone metastasis. Recently, novel androgen receptor signal inhibitors (ARSi) have been approved for metastatic castration naïve (mCNPC), or non-metastatic castration resistant prostate cancer (nmCRPC), both of which should be pivotal to investigate the association between bone microenvironment and tumor. We established a novel 3D in vitro culture method reflecting bone microenvironment and evaluated the drug susceptibility of ARSi including enzalutamide, apalutamide, darolutamide, and abiraterone (Abi) with/without dutasteride (Duta). METHODS: GFP-transferred C4-2 (CRPC cell line) and RFP-transferred human osteoblast differentiated from human-mesenchymal stem cell was co-cultured in chitosan nanofiber, a mimicry of 3D scaffold of bone microenvironment, coated culture plate (Cosmo bio Co., LTD). The growth of C4-2 cell was quantified using live-cell imaging and analysis system, Cell3 iMager duos (SCREEN). Abi metabolites including delta-4 abiraterone (D4A) and 3-keto-5-alfa abiraterone in C4-2 cells were measured by ESI-TOF-MS method. RESULTS: We could non-invasively quantify the sustained growth of C4-2 cells at maximum of 30 days. IC50 of each drugs and combination effect of Abi and Duta was evaluated using this model. Combination treatment synergistically inhibited the growth of C2-4 cells compared with each drug alone. D4A, the strongest anti-proliferative metabolite of Abi under the CRPC-specific backdoor pathway, was detected from the treated C4-2 cell. These results were coincided with the effective cases of pharmacokinetics of Abi metabolites in our ongoing phase II clinical trial of combination therapy of Abi with Duta for CRPC (UMIN000027795). Furthermore, combination of abiraterone and dutasteride was most potent cell growth inhibitor than other ARis tested in this model. This model is applying for international patent (C12N 5/09). CONCLUSIONS: Our bone microenvironment model is unique and useful to evaluate the new drug susceptibility testing in prostate cancer cells. This model may help in disclose unknown mechanisms from micro- to clinical bone metastasis in prostate cancer. Citation Format: Masahiro Samoto, Hiroaki Matsumoto, Hiroshi Hirata, Sho Ozawa, Junichi Mori, Ryo Inoue, Seiji Yano, Yoshiaki Yamamoto, Hideyasu Matsuyama. Novel bone microenvironment model of prostate cancer with chitosan fiber matrix and osteoblast in 3D culture [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 321.

Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer

Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the Cmax, Ka, t1/2, AUC(0−t) and AUC(0−∞) of troxipide were significantly increased in rats with GU compared with NC rats. The Vz, K10 and absolute bioavailability of troxipide were obviously decreased in rats with GU compared with NC rats, and its tissue distribution (in the liver, lung and kidney) was significantly different between the two groups of rats. Additionally, the pharmacodynamic results suggested that the levels of biochemical factors (IL-17, IL-6, TNF-α, IFN-γ, AP-1, MTL, GAS, and PG-II) were significantly increased, the PG-Ӏ level was obviously decreased, and the protein expression levels of HSP-90, C-Cas-3 and C-PARP-1 were markedly increased in rats with GU compared with NC rats. The above results suggested that the therapeutic mechanisms underlying the metabolic, pharmacokinetic and pharmacological properties of troxipide in vivo in rats deserve further attention based on the importance of troxipide in the treatment of GU in this study, and these mechanisms could be targets for future studies.

Influence of Drug-Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV.

BackgroundPeople living with HIV (PLWH) are aging and experience age-related physiological changes and comorbidities. Atorvastatin is a widely prescribed lipid-lowering agent metabolized by cytochrome P450 (CYP) 3A4, whose hepatocyte uptake is facilitated by organic anion transporting polypeptide (OATP) 1B1/1B3. Inhibition or induction of this enzyme and hepatic transporter can increase or decrease atorvastatin exposure, respectively.ObjectiveThis study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug–drug interactions (DDIs) with antiretrovirals (ARVs).MethodsThe atorvastatin pharmacokinetic profile was best described by a two-compartment model with first-order absorption and elimination. Metabolite concentrations were described by considering both linear metabolism from atorvastatin and presystemic metabolism. The influence of demographic and clinical covariates on drug and metabolite pharmacokinetics was assessed using NONMEM®. Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs.ResultsFull pharmacokinetic profiles (98 atorvastatin + 62 o-OH-atorvastatin concentrations) and sparse concentrations (78 and 53 for atorvastatin and o-OH-atorvastatin, respectively) were collected in 59 PLWH. Interindividual variability was high. The coadministration of boosted ARVs decreased atorvastatin clearance by 58% and slowed down o-OH-atorvastatin formation by 88%. Atorvastatin clearance increased by 78% when coadministered with CYP3A4 inducers. Simulations revealed a 180% increase and 44% decrease in atorvastatin exposure (area under the curve) in the presence of ARVs with inhibiting and inducing properties, respectively.ConclusionThis study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00876-0) contains supplementary material, which is available to authorized users.

Impact of CYP2D6*10 on venlafaxine and its desmethylated metabolite pharmacokinetics in Japanese psychiatric patients

Impact of CYP2D6*10 on venlafaxine and its desmethylated metabolite pharmacokinetics in Japanese psychiatric patients

Abstract A113: Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects

Abstract Introduction: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. The primary objectives of this phase 1, open-label study in healthy male subjects were to characterize the absorption, metabolism, and excretion of 14C-napabucasin and to determine the pharmacokinetics of 14C-napabucasin and relevant metabolites in plasma, urine, and feces. The secondary objective was to assess safety and tolerability of napabucasin. Methods: Healthy male adult (age 18–45 years) subjects were eligible to receive a single oral 240-mg dose of napabucasin containing ~100 μCi of 14C-napabucasin. Blood, urine, and feces were collected up to 264 hours (h; 11 days) postdose. Whole blood, plasma, urine, fecal, and expired air samples were assayed for total radioactivity (TR). Plasma, urine, and fecal samples were assayed for napabucasin and metabolites. Results: Overall, 8 subjects (mean [range] age 29 [23–39] years) were enrolled. The mean TR recovered was 81.1%. In general, elimination of 14C-napabucasin was predominantly via feces (57.2%), to a lesser extent via urine (23.8%), and was negligible in expired air. Most (76.0%) recovery was within 48 h postdose. 14C-napabucasin was rapidly absorbed (median time to peak concentration 2.8 h) and underwent extensive reductive metabolism to yield dihydro-napabucasin (M1), the sole major circulating metabolite. Systemic exposure to 14C-napabucasin was higher than M1, and M1 plasma concentration versus time profiles generally mirrored 14C-napabucasin. Similar arithmetic mean half-lives for 14C-napabuscasin and M1 (7.9 h and 7.1 h, respectively) suggest that the rate of formation of the reduced metabolite is rate limiting. The TR whole blood:plasma ratio of 0.4 indicated that circulating drug-related compounds were essentially confined to plasma. Four minor metabolites were identified but accounted for ≤7.0% of TR in plasma. Consistent with preclinical animal models, no uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites. These data suggest that 14C-napabucasin was mainly cleared by reductive metabolism and, to a lesser extent, by renal elimination. 14C-napabucasin and M1 recovered in urine accounted for 13.2% and 9.6% of the administered dose, respectively. Apparent renal clearance of 14C-napabucasin and M1 were 8.1 L/h and 7.9 L/h, respectively. All subjects experienced treatment-emergent adverse events (TEAEs). All TEAEs were mild (grade 1) and the majority were assessed as related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders and, of these, diarrhea was reported most frequently and generally started within 4.5–5.0 h postdose and resolved without treatment. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Conclusions: 14C-napabucasin is primarily excreted through feces. 14C-napabucasin underwent extensive metabolism to yield M1 as the sole major circulating metabolite. No uniquely human or disproportionate metabolite was quantified. A single oral 240-mg dose of napabucasin was tolerated in healthy male subjects. Citation Format: Xiaoshu Dai, Michael D Karol, Matthew Hitron, Marjie Hard, J Evan Blanchard, Nicola Eraut, Natalie Rich, Brandon Gufford. Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A113. doi:10.1158/1535-7163.TARG-19-A113

Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis.

Capecitabine is an oral prodrug of the anticancer drug 5‐fluorouracil (5‐FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5′‐deoxy‐5‐fluorocytidine (dFCR), 5′‐deoxy‐5‐fluorouridine (dFUR), 5‐FU, and fluoro‐β‐alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four‐transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two‐compartment models, and dFUR and 5‐FU were subject to flip‐flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5‐FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.

Treosulfan Metabolite (S, S-EBDM) Pharmacokinetics Influences Regimen Related Toxicity in Patients with Beta Thalassaemia Major Undergoing HSCT

A toxicity reduced conditioning regimen containing Treosulfan (Treo), Fludarabine (Flu), Thiotepa in patients with class III high risk thalassemia major (TM) has significantly improved transplant outcomes compared to the historical Busulfan/cyclophosphamide based myeloablative regimen (Mathews et al, 2013). However, complications related to mixed chimerism, rejection and regimen related toxicity remain. Analysis of Treo pharmacokinetics (PK) in TM showed significant inter individual variation but no association with HSCT outcome (Mohanan et al, 2018). This may be attributed to the fact that only the pro-drug Treo was measured and not its active metabolites. Treo, administered as a prodrug, is converted non-enzymatically to its active metabolite monoepoxide 2S, 3S-1,2-epoxybutane-3,4-diol-4-methanesulfonate (S, S-EBDM) and (2S,3S)- 1,2:3,4-diepoxybutane (S, S-DEB) that causes cytotoxicity. We have now assessed the PK of both Treo and S, S-EBDM and the factors which may influence the inter-individual variation in PK, and their impact on HSCT outcome in patients with TM. Fifty-six patients with TM undergoing HSCT between January 2016 and June 2019 with Flu/Treo based conditioning regimen (Flu 40mg/m2/day x 4 days as a 1hr infusion and Treo as 14g/m2/day x 3 days infused at 5g/hr) were included in this analysis. Selected functional polymorphisms in NAD(P)H Quinone Dehydrogenase-1 (NQO1) and Glutathione S-transferase (GST) genes that showed association with Treo PK based on our previous report (Pai et al, Abstract. Proceedings of BMT Tandem Meetings 2018) were screened. Plasma Treo and S, S-EBDM were measured using an LC-MS/MS method. Treo and S, S-EBDM PK were estimated using nonlinear mixed effects modeling via Monolix 5.0.1. The covariates tested were age, sex, body weight, BSA, serum ferritin, NQO1 3'UTR (rs10517) and GSTA1*B polymorphisms. The influence of Treo &amp; S, S-EBDM PK and polymorphisms on graft rejection, regimen related toxicities (RRT), chimerism status, overall and event-free survival were estimated using logistic regression analysis. A two-compartment model best described the PK of Treo and S, S-EBDM. Two and 11-fold inter-individual variation was observed in Treo and S, S-EBDM PK respectively. Among the covariates tested, Treo Cl decreased with age (p=0.03) while, S, S-EBDM apparent Cl increased in patients with NQO1 3'UTR variant (p=0.02) and decreased in patients with GSTA1*B variant genotype (p=0.02). Neither Treo AUC nor clearance showed association with HSCT outcome. However, high S, S-EBDM AUC (213. Vs 130 mg*hr/mL, p=0.016) and low S, S-EBDM apparent Cl (68 Vs 122 L/hr/m2, p=0.013) were significantly associated with increased incidence of sinusoidal obstruction syndrome (SOS). Also, on quartile analysis, patients with S, S-EBDM AUC &gt;210 mg*hr/mL and Treo/S, S-EBDM AUC ratio &gt;18 mg*hr/mL showed increased incidence of SOS (p=0.006 &amp; p=0.026 respectively). Multivariate analysis adjusting for known clinical risk factors also showed in addition to age, only high S, S-EBDM AUC to be significantly associated with increased incidence of SOS (p=0.013). No association between rejection or mixed chimerism and Treo/S, S-EBDM PK was observed, probably due to very low incidence of graft rejection in this cohort (4/56; 7%). Our study suggests that active metabolite S, S-EBDM influences SOS following HSCT in TM patients. It is well acknowledged that Treo to S, S-EBDM conversion is a non-enzymatic nucleophilic substitution reaction and there is a difference in the disposition of Treo and S, S-EBDM in different organs including the liver (Romanski et al, 2017). Treo metabolites exert their cytotoxic activity by both DNA-DNA and DNA-protein crosslinks in these organs. The role of Treo metabolites in exhausting essential cellular proteins like GSH and NQO1 as well as the effect of GST/NQO1 variants in influencing Treo metabolism in liver which may then impact the incidence and severity of SOS need further evaluation. Disclosures No relevant conflicts of interest to declare.

Gut Microbiota-Mediated Drug-Drug Interaction between Amoxicillin and Aspirin

The effects of antibiotics on the intestinal flora can create potential drug-drug interactions. The combination of amoxicillin and aspirin is high and there is a high probability of interaction. We used 16S rRNA, incubation experiments and liquid chromatography-tandem mass spectrometry to analyze rat biological samples to characterize the effect of amoxicillin on the pharmacokinetics of aspirin metabolites. We first discovered that amoxicillin reduced the species and number of intestinal flora in rats, such as reducing the abundance of Helicobacter pylori and Prevotella_copri. After 12, 24, and 36 hours of incubation, the remaining amount of aspirin in the aspirin and amoxicillin treatment groups decreased, and salicylic acid production increased, suggesting that aspirin is metabolized by the intestinal flora, and the main metabolite is salicylic acid. As the incubation time prolonged, the reduction of aspirin and the production of salicylic acid in the amoxicillin treatment group were slower. It is indicated that the metabolic activity of aspirin through the intestinal flora is slowed down after administration of amoxicillin. The pharmacokinetic experiments showed that after administration of amoxicillin, the area under the salicylic acid curve increased by 91.38%, the peak concentration increased by 60.43%, and the clearance rate decreased by 43.55%.The results demonstrated that amoxicillin affected the pharmacokinetics of aspirin active metabolite salicylic acid by slowing down the metabolic activity of intestinal flora on aspirin. The interaction between amoxicillin and aspirin mediated by the intestinal flora may affect the efficacy of aspirin and cause more significant adverse effects.

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization

Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.

Development of Validated Methods and Quantification of Curcuminoids and Curcumin Metabolites and Their Pharmacokinetic Study of Oral Administration of Complete Natural Turmeric Formulation (Cureit™) in Human Plasma via UPLC/ESI-Q-TOF-MS Spectrometry.

Specific and sensitive ultra-high performance liquid chromatography-quadrupole time of flight-mass spectroscopy (UPLC-QTOF-MS) methods have been developed for the determination of curcuminoids and curcumin metabolites in human blood plasma. The UPLC-QTOF-MS method used a binary solvent delivery system and the chromatographic separation was performed on a C-18 (2.1 × 50 mm; 1.7 µm) column. Mass spectra were obtained on a Waters Xevo G2S Q-TOF mass spectrometer. The developed methods to characterize the pharmacokinetics of curcuminoids and curcumin metabolites in human blood plasma after an oral administration of bioavailable curcumin—Cureit™—were validated. It was found that the complete turmeric matrix enhances the concentration of tetrahydrocurcumin (THC), hexahydrocurcumin (HHC), octahydrocurcumin (OHC), curcumin-O-glucuronide (COG) and curcumin-O-sulfate (COS) in the blood plasma once the product is administrated.