Total Drug Clearance Research Articles

An Investigational Study on the Role of CYP2D6, CYP3A4 and UGTs Genetic Variation on Fesoterodine Pharmacokinetics in Young Healthy Volunteers.

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (Cmax/DW)), elimination (terminal half-life (T1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and Cmax/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and Cmax/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, Cmax, and CL/F of 5-HMT, which should be confirmed in other studies.

Interaction of Depot Medroxyprogesterone Acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood Mononuclear Cells and Cervical Tissue Susceptibility to HIV Infection and Pharmacokinetics.

Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is highly effective in reducing HIV acquisition in women. We sought to determine the impact of DMPA on F/TDF pharmacokinetics and pharmacodynamics. Twelve healthy premenopausal cisgender women were enrolled and each completed 4 sequential conditions: (1) baseline, (2) steady-state F/TDF alone, (3) steady-state F/TDF + DMPA, and (4) DMPA alone. Assessments included clinical, pharmacokinetic, viral infectivity (ex vivo challenge of peripheral blood mononuclear cells by X4- and R5-tropic green fluorescent protein pseudoviruses and cervical tissue by HIV BaL ), endocrine, immune cell phenotyping, and renal function. Compared with baseline, F/TDF (± DMPA) significantly decreased both %R5- and X4-infected CD4 T cells and F/TDF + DMPA decreased cervical explant p24 (all P < 0.05). The %R5- and X4-infected CD4 T cells were higher during DMPA alone than during F/TDF periods and lower than baseline (not statistically significant). Cervical explant p24 fell between baseline and F/TDF values (not statistically significant). There were neither statistically significant differences in F/TDF pharmacokinetics, including total or renal clearance of either antiviral drug, nor changes in glomerular filtration rate with the addition of DMPA. There were few immune cell phenotypic differences across conditions. F/TDF decreased HIV infection in both challenge assays, whereas DMPA alone did not enhance HIV infection in either challenge assay. DMPA did not alter F/TDF pharmacokinetics or renal function.

Predicting Total Drug Clearance and Volumes of Distribution Using the Machine Learning-Mediated Multimodal Method through the Imputation of Various Nonclinical Data

Pharmacokinetic research plays an important role in the development of new drugs. Accurate predictions of human pharmacokinetic parameters are essential for the success of clinical trials. Clearance (CL) and volume of distribution (Vd) are important factors for evaluating pharmacokinetic properties, and many previous studies have attempted to use computational methods to extrapolate these values from nonclinical laboratory animal models to human subjects. However, it is difficult to obtain sufficient, comprehensive experimental data from these animal models, and many studies are missing critical values. This means that studies using nonclinical data as explanatory variables can only apply a small number of compounds to their model training. In this study, we perform missing-value imputation and feature selection on nonclinical data to increase the number of training compounds and nonclinical datasets available for these kinds of studies. We could obtain novel models for total body clearance (CLtot) and steady-state Vd (Vdss) (CLtot: geometric mean fold error [GMFE], 1.92; percentage within 2-fold error, 66.5%; Vdss: GMFE, 1.64; percentage within 2-fold error, 71.1%). These accuracies were comparable to the conventional animal scale-up models. Then, this method differs from animal scale-up methods because it does not require animal experiments, which continue to become more strictly regulated as time passes.

ZY12201, A Potent TGR5 Agonist: Identification of a Novel Pan CYP450 Inhibitor Tool Compound for In-Vitro Assessment.

Identification of clinical drug-drug interaction (DDI) risk is an important aspect of drug discovery and development owing to poly-pharmacy in present-day clinical therapy. Drug metabolizing enzymes (DME) plays important role in the efficacy and safety of drug candidates. Hence evaluation of a New Chemical Entity (NCE) as a victim or perpetrator is very crucial for DDI risk mitigation. ZY12201 (2-((2-(4-(1H-imidazol-1-yl) phenoxy) ethyl) thio)-5-(2-(3, 4- dimethoxy phenyl) propane-2-yl)-1-(4-fluorophenyl)-1H-imidazole) is a novel and potent Takeda-G-protein-receptor-5 (TGR-5) agonist. ZY12201 was evaluated in-vitro to investigate the DDI liabilities. The key objective was to evaluate the CYP inhibition potential of ZY12201 for an opportunity to use it as a tool compound for pan CYP inhibition activities. In-vitro drug metabolizing enzymes (DME) inhibition potential of ZY12201 was evaluated against major CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5), aldehyde oxidase (AO), monoamine oxidase (MAO), and flavin-containing monooxygenase (FMO in human liver cytosol/mitochondrial preparation/ microsomes using probe substrates and Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) method. The study conducted on ZY12201 at 100 µM ZY12201 was found to reduce the metabolism of vanillin (AO probe substrate), tryptamine (MAO probe substrate), and benzydamine (FMO probe substrate) by 49.2%, 14.7%, and 34.9%, respectively. ZY12201 Ki values were 0.38, 0.25, 0.07, 0.01, 0.06, 0.02, 7.13, 0.03 and 0.003 μM for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 (substrate: testosterone) and CYP3A4/5 (substrate: midazolam), respectively. Time-dependant CYP inhibition potential of ZY12201 was assessed against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 and no apparent IC50 shift was observed. ZY12201, at 100 µM concentration showed low inhibition potential of AO, MAO, and FMO. ZY12201 was found as a potent inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 while moderately inhibits to CYP2E1. Inhibition of CYP1A2, CYP2B6, CYP2C19, and CYP2E1 by ZY12201 was competitive, while inhibition of CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5 was of mixed-mode. ZY12201 is a non-time-dependent inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5. In summary, the reported Ki values unequivocally support that ZY12201 has a high potential to inhibit all major CYP isoforms. ZY12201 can be effectively used as a tool compound for in-vitro evaluation of CYP-based metabolic contribution to total drug clearance in the lead optimization stage of Drug Discovery Research.

A Randomized, Open-Label, Single-Dose Study to Assess Safety and Systemic Exposure of Triamcinolone Acetonide Extended-Release in Patients With Hip Osteoarthritis.

IntroductionIntra-articular (IA) corticosteroids, including triamcinolone acetonide (TA), are a recommended treatment for hip osteoarthritis. We compared the safety and systemic exposure of TA extended-release (TA-ER) versus TA crystalline suspension (TAcs) in patients with hip osteoarthritis.MethodsIn this phase 2, randomized, multicenter, open-label, single-dose study (NCT03382262), patients with hip osteoarthritis were randomly assigned 1:1 to receive single IA injections of TA-ER 32 mg or TAcs 40 mg. Safety assessments included treatment-emergent adverse events (TEAEs). Blood samples were collected for pharmacokinetic (PK) analysis up to day 85. PK parameters included area under the concentration–time curve, total body drug clearance, maximum concentration (Cmax), mean residence time, half-life, and time to maximum concentration.ResultsOf 30 patients (TA-ER: n = 15; TAcs: n = 15) randomized and included in the Safety Population, 25 patients were evaluated in the PK Population. TEAEs were reported in four of 15 (26.7%) patients who received TA-ER and in seven of 15 (46.7%) patients who received TAcs. The most common TEAEs included arthralgia and headache. All TEAEs were of grade 1 or 2 in severity. TA-ER produced substantially lower peak plasma TA concentrations compared with TAcs (Cmax geometric mean: 890.4 vs. 5549.4 pg/ml), and these were less variable with TA-ER versus TAcs. Similarly, overall TA systemic exposure was substantially lower for TA-ER versus TAcs, with gradual elimination from systemic circulation through day 85.ConclusionsFollowing a single IA injection in the hip, TA-ER was generally well tolerated, with a safety profile comparable to that of TAcs. Systemic TA exposure was markedly lower in TA-ER-treated patients, consistent with the PK profile observed in knee osteoarthritis.Clinicaltrials.gov identifier: NCT03382262.

Personalization of drug dose thematic issue: introduction article

ABSTRACT Introduction The need to individualize a drug dosage and adjust it to a patient’s physiological and/or pathophysiological status is rarely satisfied in routine clinical practice, primarily because of complexity of the adjustment task. Areas covered The aim of this article is to shed light to basic principles of drug dosage individualization in the most frequent clinical states that affect pharmacokinetics of drugs. The principles are derived from published clinical studies conducted on diverse patient populations, using non-compartmental pharmacokinetic model. Expert opinion Simple, but sufficiently exact, way to calculate appropriate drug dose for a patient is the one based on target average steady-state concentration and non-compartmental pharmacokinetic model. If target steady-state drug concentration and dosage interval are considered fixed, maintenance dose could be adjusted on the basis of expected changes of total drug clearance and bioavailability, while loading dose should be related to changes of volume of distribution and bioavailability. Relative increase or decrease of these pharmacokinetic parameters in regard to normal values in healthy persons is translated to relative (percentual) increase or decrease of maintenance and loading doses recommended in the drug monograph.

Abstract CT124: Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor

Abstract Background: The PARP inhibitor rucaparib is approved in the US for pts with recurrent ovarian or metastatic castration-resistant prostate cancer. This phase 1 study (NCT03499444) evaluated safety, pharmacokinetics (PK), and antitumor activity (per RECIST v1.1) of rucaparib in Japanese pts. Methods: Pts were enrolled in a 3+3 dose-escalation phase to establish the recommended dose (RD) in Japanese pts; dose-limiting toxicities (DLTs) were assessed in the first 21 days. Pts must have had an advanced solid tumor that had progressed on standard treatment. A dose-expansion phase enrolled pts at the RD to further assess safety, PK, and efficacy. Results: The visit cutoff was Oct 20, 2020; 29 pts received rucaparib, including 15 in the dose-escalation phase (400 mg BID, n=3; 500 mg BID, n=6; and 600 mg BID, n=6) and 14 in the dose-expansion phase at the RD of 600 mg BID. Median (range) time on treatment was 5.1 (1.3-16.4) months overall and 5.3 (1.4-16.4) months for 600 mg BID pts (n=20).One DLT was reported (treatment interruption &amp;gt;7 days due to grade 1/2 nausea, vomiting, diarrhea, fatigue; 500 mg BID cohort). Across all doses, the most frequent any-grade treatment-emergent adverse events (TEAEs) were alanine aminotransferase/aspartate aminotransferase increased (82.8%), anemia (82.8%), and nausea (69.0%); the most frequent grade ≥3 TEAE was anemia (51.7%). Among 600 mg BID pts, 25.0% (5/20) had a TEAE leading to treatment interruption or dose reduction, most commonly due to anemia (20.0%; 4/20).Steady-state PK was evaluated for the 400, 500, and 600 mg BID cohorts (Table).Most pts with measurable disease had a best response of stable disease (63.0%; 17/27); the confirmed objective response rate was 18.5% (5/27) overall and 21.1% (4/19) among 600 mg BID pts (Table).Conclusions: Rucaparib 600 mg BID had a manageable safety profile for Japanese pts with advanced solid tumors, with a PK profile similar to that of Western pts. These results support further exploration of rucaparib in Japanese pts. 400 mg BID(n=3)500 mg BID(n=6)600 mg BID(n=20)Overall(N=29)Baseline characteristicsAge, median (range), years67.0 (45.0-68.0)61.5 (44.0-73.0)59.5 (43.0-74.0)61.0 (43.0-74.0)Female, n (%)3 (100)6 (100)16 (80.0)25 (86.2)ECOG PS 0, n (%)a3 (100)4 (66.7)15 (75.0)22 (75.9)Tumor type, n (%)Ovarian2 (66.7)1 (16.7)9 (45.0)12 (41.4)Primary peritoneal1 (33.3)2 (33.3)2 (10.0)5 (17.2)Pancreatic004 (20.0)4 (13.8)Breast02 (33.3)1 (5.0)3 (10.3)Other01 (16.7)4 (20.0)5 (17.2)Steady-state PK dataCmax, mean (CV%), ng/mL1,690 (38.7)3,650 (61.9)b2,800 (37.0)cNCtmax, median (range), h1.48 (1.47-2.45)3.95 (2.47-9.95)b2.50 (0.93-9.83)cNCCmin, mean (CV%), ng/mL1,590 (38.7)2,380 (78.5)2,130 (44.4)NCAUClast, mean (CV%), h × ng/mL14,400 (36.6)30,200 (64.7)b23,800 (39.9)cNCCL/F, mean (CV%), L/h26.1 (45.2)22.1 (68.5)d24.3 (34.6)eNCAUC0-12, mean (CV%), h × ng/mL17,200 (35.8)33,900 (78.9)d28,100 (40.8)eNCEfficacy dataORR, n/N (%) [95% CI]1/3 (33.3) [0.8-90.6]0/5 (0) [0.0-52.2]4/19 (21.1) [6.1-45.6]5/27 (18.5) [6.3-38.1]aAll other pts had ECOG PS 1.bn=5.cn=18.dn=3.en=13.AUC0-12, area under the concentration-time curve up to 12 h; AUClast, area under the concentration-time curve up to last time point (10 h) with a quantifiable concentration; CL/F, apparent total clearance of drug after oral administration; Cmax, maximum concentration; CV, coefficient of variation; ECOG PS, Eastern Cooperative Oncology Group performance status; NC, not calculated; ORR, objective response rate; PK, pharmacokinetics; tmax, time to maximum concentration. Citation Format: Kenji Tamura, Koji Matsumoto, Kan Yonemori, Kosei Hasegawa, Jenn Habeck, Eric Jones, Jim Xiao, Aaron Enke, Keiichi Fujiwara. Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT124.

Development of Robust Quantitative Structure-Activity Relationship Models for CYP2C9, CYP2D6, and CYP3A4 Catalysis and Inhibition.

Cytochrome P450 enzymes are responsible for the metabolism of >75% of marketed drugs, making it essential to identify the contributions of individual cytochromes P450 to the total clearance of a new candidate drug. Overreliance on one cytochrome P450 for clearance levies a high risk of drug-drug interactions; and considering that several human cytochrome P450 enzymes are polymorphic, it can also lead to highly variable pharmacokinetics in the clinic. Thus, it would be advantageous to understand the likelihood of new chemical entities to interact with the major cytochrome P450 enzymes at an early stage in the drug discovery process. Typical screening assays using human liver microsomes do not provide sufficient information to distinguish the specific cytochromes P450 responsible for clearance. In this regard, we experimentally assessed the metabolic stability of ∼5000 compounds for the three most prominent xenobiotic metabolizing human cytochromes P450, i.e., CYP2C9, CYP2D6, and CYP3A4, and used the data sets to develop quantitative structure-activity relationship models for the prediction of high-clearance substrates for these enzymes. Screening library included the NCATS Pharmaceutical Collection, comprising clinically approved low-molecular-weight compounds, and an annotated library consisting of drug-like compounds. To identify inhibitors, the library was screened against a luminescence-based cytochrome P450 inhibition assay; and through crossreferencing hits from the two assays, we were able to distinguish substrates and inhibitors of these enzymes. The best substrate and inhibitor models (balanced accuracies ∼0.7), as well as the data used to develop these models, have been made publicly available (https://opendata.ncats.nih.gov/adme) to advance drug discovery across all research groups. SIGNIFICANCE STATEMENT: In drug discovery and development, drug candidates with indiscriminate cytochrome P450 metabolic profiles are considered advantageous, since they provide less risk of potential issues with cytochrome P450 polymorphisms and drug-drug interactions. This study developed robust substrate and inhibitor quantitative structure-activity relationship models for the three major xenobiotic metabolizing cytochromes P450, i.e., CYP2C9, CYP2D6, and CYP3A4. The use of these models early in drug discovery will enable project teams to strategize or pivot when necessary, thereby accelerating drug discovery research.

Influence of Pyrexia on Pharmacokinetics of Azithromycin and Its Interaction With Tolfenamic Acid in Goats.

Azithromycin is a macrolide antimicrobial agent of the azalide group with a broad spectrum of activity against gram-negative and gram-positive bacterial organisms. Tolfenamic acid is a non-steroidal anti-inflammatory drug of the fenamate group, which is used extensively in humans and animals due to its anti-inflammatory, analgesic, and antipyretic properties. There is dearth of literature on any type of drug interaction between azithromycin and tolfenamic acid in any species, including human beings and alteration of its pharmacokinetics by fever. Therefore, the objective of this study was to investigate the alteration of disposition kinetics of azithromycin alone and in the presence of tolfenamic acid in Malabari goats by fever, following an intravenous administration at a dose rate of 20 mg/kg body weight. Blood samples collected from both afebrile and febrile goats at predetermined time intervals after the administration of azithromycin alone and then in combination with tolfenamic acid (2 mg/kg, intravenously), respectively, were analyzed using high-performance liquid chromatography. Non-compartmental analysis was used to determine the peak blood concentration (Cmax), time-to-peak plasma concentration (Tmax), half-life (t1/2λz), area under the curve (AUC 0−t, AUC 0−inf), area under the first moment curve (AUMC 0−inf), mean residence time (MRT0−inf), apparent volume of distribution at steady state (Vss), and the total body clearance of drug from the blood (Cl). In febrile animals, significant differences were noted in the values of Cmax, Cl, and Vss. Thus, azithromycin disappears into an additional compartment in febrile goats, which may be due to its extended cellular penetration into the inflammatory cells, resulting in anti-inflammatory activity. Tolfenamic acid significantly altered the pharmacokinetics of azithromycin in both normal and febrile animals. Tolfenamic acid, being a better anti-inflammatory agent, suppresses the inflammatory mediators, reducing the possibility of increased utilization of azithromycin in febrile condition.

Prediction of Total Drug Clearance in Humans Using Animal Data: Proposal of a Multimodal Learning Method Based on Deep Learning.

Research into pharmacokinetics plays an important role in the development process of new drugs. Accurately predicting human pharmacokinetic parameters from preclinical data can increase the success rate of clinical trials. Since clearance (CL) which indicates the capacity of the entire body to process a drug is one of the most important parameters, many methods have been developed. However, there are still rooms to be improved for practical use in drug discovery research; "improving CL prediction accuracy" and "understanding the chemical structure of compounds in terms of pharmacokinetics". To improve those, this research proposes a multimodal learning method based on deep learning that takes not only the chemical structure of a drug but also rat CL as inputs. Good results were obtained compared with the conventional animal scale-up method; the geometric mean fold error was 2.68 and the proportion of compounds with prediction errors of 2-fold or less was 48.5%. Furthermore, it was found to be possible to infer the partial structure useful for CL prediction by a structure contributing factor inference method. The validity of these results of structural interpretation of metabolic stability was confirmed by chemists.

Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure

Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers. PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions. Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies. Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category. Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies. In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.

Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli.

Cefiderocol is an injectable siderophore cephalosporin discovered and being developed by Shionogi & Co., Ltd., Japan. As with other β-lactam antibiotics, the principal antibacterial/bactericidal activity of cefiderocol occurs by inhibition of Gram-negative bacterial cell wall synthesis by binding to penicillin binding proteins; however, it is unique in that it enters the bacterial periplasmic space as a result of its siderophore-like property and has enhanced stability to β-lactamases. The chemical structure of cefiderocol is similar to both ceftazidime and cefepime, which are third- and fourth-generation cephalosporins, respectively, but with high stability to a variety of β-lactamases, including AmpC and extended-spectrum β-lactamases (ESBLs). Cefiderocol has a pyrrolidinium group in the side chain at position 3 like cefepime and acarboxypropanoxyimino group in the side chain at position 7 of the cephem nucleus like ceftazidime. The major difference in the chemical structures of cefiderocol, ceftazidime and cefepime is the presence of a catechol group on the side chain at position 3. Together with the high stability to β-lactamases, including ESBLs, AmpC and carbapenemases, the microbiological activity of cefiderocol against aerobic Gram-negative bacilli is equal to or superior to that of ceftazidime-avibactam and meropenem, and it is active against a variety of Ambler class A, B, C and D β-lactamases. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem versus Acinetobacter baumannii, including meropenem non-susceptible and multidrug-resistant (MDR) isolates. Cefiderocol's activity against meropenem-non-susceptible and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriales is comparable or superior to ceftazidime-avibactam. Cefiderocol is also more potent than both ceftazidime-avibactam and meropenem against all resistance phenotypes of Pseudomonas aeruginosa and against Stenotrophomonas maltophilia. The current dosing regimen being used in phase III studies is 2g administered intravenously every 8h (q8h) using a 3-h infusion. The pharmacokinetics of cefiderocol are best described by a three-compartment linear model. The mean plasma half-life (t½) was ~ 2.3h, protein binding is 58%, and total drug clearance ranged from 4.6-6.0 L/h for both single- and multi-dose infusions and was primarily renally excreted unchanged (61-71%). Cefiderocol is primarily renally excreted unchanged and clearance correlates with creatinine clearance. Dosage adjustment is thus required for both augmented renal clearance and in patients with moderate to severe renal impairment. In vitro and in vivo pharmacodynamic studies have reported that as with other cephalosporins the pharmacodynamic index that best predicts clinical outcome is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC). In vivo efficacy of cefiderocol has been studied in a variety of humanized drug exposure murine and rat models of infection utilizing a variety of MDR and extremely drug resistant strains. Cefiderocol has performed similarly to or has been superior to comparator agents, including ceftazidime and cefepime. A phase II prospective, multicenter, double-blind, randomized clinical trial assessed the safety and efficacy of cefiderocol 2000mg q8h versus imipenem/cilastatin 1000mg q8h, both administered intravenously for 7-14days over 1h, in the treatment of complicated urinary tract infection (cUTI, including pyelonephritis) or acute uncomplicated pyelonephritis in hospitalized adults. A total of 452 patients were initially enrolled in the study, with 303 in the cefiderocol arm and 149 in the imipenem/cilastatin arm. The primary outcome measure was a composite of clinical cure and microbiological eradication at the test-of-cure (TOC) visit, that is, 7days after the end of treatment in the microbiological intent-to-treat (MITT) population. Secondary outcome measures included microbiological response per pathogen and per patient at early assessment (EA), end of treatment (EOT), TOC, and follow-up (FUP); clinical response per pathogen and per patient at EA, EOT, TOC, and FUP; plasma, urine and concentrations of cefiderocol; and the number of participants with adverse events. The composite of clinical and microbiological response rates was 72.6% (183/252) for cefiderocol and 54.6% (65/119) for imipenem/cilastatin in the MITT population. Clinical response rates per patient at the TOC visit were 89.7% (226/252) for cefiderocol and 87.4% (104/119) for imipenem/cilastatin in the MITT population. Microbiological eradication rates were 73.0% (184/252) for cefiderocol and 56.3% (67/119) for imipenem/cilastatin in the MITT population. Additionally, two phase III clinical trials are currently being conducted by Shionogi & Co., Ltd., Japan. The two trials are evaluating the efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens and evaluating the efficacy of cefiderocol in the treatment of adults with hospital-acquired bacterial pneumonia, ventilator-associated pneumonia or healthcare-associated pneumonia caused by Gram-negative pathogens. Cefiderocol appears to be well tolerated (minor reported adverse effects were gastrointestinal and phlebitis related), with a side effect profile that is comparable to other cephalosporin antimicrobials. Cefiderocol appears to be well positioned to help address the increasing number of infections caused by carbapenem-resistant and MDR Gram-negative bacilli, including ESBL- and carbapenemase-producing strains (including metallo-β-lactamase producers). A distinguishing feature of cefiderocol is its activity against resistant P. aeruginosa, A. baumannii, S. maltophilia and Burkholderia cepacia.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Meropenem in Critically Ill Young Children.

This study aims to describe the population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill children. The study involved a retrospective medical record review from a 189-bed, freestanding children's tertiary care teaching hospital of patients ages 1 to 9 years who received meropenem with concurrent therapeutic drug monitoring. There were 9 patients ages 1 to 9 years (mean age, 3.1 ± 2.9 years) with a mean weight of 17.1 ± 11.9 kg who met the inclusion/exclusion criteria and were included in the pharmacokinetic analysis. Meropenem concentrations were best described by a 2-compartment model with first-order elimination, with an R2 and bias of 0.91 and 13.2 mg/L, respectively, for the observed versus population predicted concentrations, and an R2, bias, and imprecision of 1, 0.0675, and 1 mg/L, respectively, for the observed versus individual predicted concentrations. The mean total body drug clearance for the population was 6.99 ± 2.5 mL/min/kg, and Vc was 0.57 ± 0.47 L/kg. The calculated population estimate for the total volume of distribution was 0.78 ± 0.73 L/kg. Standard 0.5-hour meropenem infusions did not provide for appropriate pharmacodynamic exposures of 40% free time > minimum inhibitory concentration (40% fT > MIC) for Gram-negative organisms with susceptible MICs. Dosage regimens employing prolonged and continuous infusion regimens did provide appropriate pharmacodynamic exposures of 40% fT > MIC for Gram-negative organisms up to the break point for Pseudomonas aeruginosa of 4 mg/L. These data suggest the reference dosage regimens for meropenem (20-40 mg/kg per dose every 8 hours) do not meet an appropriate pharmacodynamic target attainment in critically ill children ages 1 to 9 years. Based on these data, only the 3- to 4-hour prolonged infusion and 24-hour continuous infusion regimens were able to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 40% fT > MIC. Dosage regimens of 120 and 160 mg/kg/day as continuous infusion regimens may be necessary to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 80% fT > MIC. Based on these findings, confirmation with a larger, prospective investigation in critically ill children is warranted.

Individualised antimicrobial dosing in critically ill patients undergoing continuous renal replacement therapy: focus on total drug clearance

BackgroundContinuous renal replacement therapy (CRRT) is common practice in critical care patients with acute renal failure.ObjectivesTo evaluate the adequacy of antimicrobial doses calculated based on the total drug clearance and...

A cell-level model of pharmacodynamics-mediated drug disposition.

We aimed to develop a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model to analyze in vivo systems where the PD response to a drug has an appreciable effect on the pharmacokinetics (PK). An existing cellular level model of PD stimulation was combined with the standard target-mediated drug disposition (TMDD) model and the resulting model structure was parametrically identifiable from typical in vivo PK and PD data. The PD model of the cell population was controlled by the production rate k in and elimination rate k out which could be stimulated or inhibited by the number of bound receptors on a single cell. Simulations were performed to assess the impact of single and repeated dosing on the total drug clearance. The clinical utility of the cell-level PDMDD model was demonstrated by fitting published data on the stimulatory effects of filgrastim on absolute neutrophil counts in healthy subjects. We postulated repeated dosing as a means of detecting and quantifying PDMDD as a single dose might not be sufficient to elicit the cellular response capable of altering the receptor pool to visibly affect drug disposition. In the absence of any PD effect, the model reduces down to the standard TMDD model. The applications of this model can be readily extended to include chemotherapy-induced cytopenias affecting clearance of endogenous hematopoietic growth factors, different monoclonal antibodies and immunogenicity effects on PK.

Slow drug delivery decreased total body clearance and altered bioavailability of immediate- and controlled-release oxycodone formulations.

Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate‐release or controlled‐release formulations, under different administration routes, and in diverse populations. Longer terminal half‐lives from extravascular administration as compared to IV administration have been attributed to flip‐flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip‐flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time‐varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half‐lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate‐dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip‐flop and offered new insight for the development of modified release formulations and clinical use of oxycodone.

Effect of continuous renal replacement therapy on the plasma concentration of imipenem in severe infection patients with acute renal injury

To investigate the extracorporeal clearance rate of imipenem in severe infection patients in the mode of continuous vena-venous hemofiltration (CVVH) during continuous renal replacement therapy (CRRT), in order to approach if the concentration of imipenem in plasma could achieve effective levels of anti-infection, and to explore the effect of time and anticoagulation measure on imipenem clearance during CRRT treatment. A prospective observational study was conducted. All adult severe infection patients complicating acute kidney injury (AKI) in the Department of Critical Care Medicine of the Fourth Hospital of Hebei Medical University from March 2013 to September 2014, who were prescribed imipenem as part of their required medical care, and CRRT for treatment of AKI were enrolled. 0.5 g doses of imipenem was administered intravenously every 6 hours or 8 hours according to random number table, and infused over 0.5 hour. The unfractionated heparin was used for anticoagulation in the patients without contraindications, and no anticoagulation strategy was used in the patients with high risk of bleeding. At 24 hours after first time of administration, postfilter venous blood and ultrafiltrate samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 5, 6, and 8 hours after imipenem administration. The concentration of imipenem in above samples was determined with liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS). A total of 25 patients were enrolled. Thirteen patients received imipenem intravenously every 6 hours, and 12 patients, every 8 hours. The anticoagulation was conducted with heparin in 13 cases, and 12 cases without anticoagulation. The intra-day precision, inter-day precision, matrix effect, and recovery rate in low, medium, and high concentration of plasma and ultrafiltrate, and the stability of samples under different conditions showed a good result, the error of accuracy was controlled in the range of ±15%. With the application of Prismaflex blood filtration system and AN69-M100 filter, under the mode with CVVH, the total clearance rate of imipenem was (8.874±2.828) L/h when the actual dose of replacement fluid was (31.63±1.48) mL×kg⁻¹×h⁻¹, the total CRRT clearance rate of imipenem in vitro was (2.211±0.539) L/h, which accounting for (30.1±15.7)% of the total drug clearance. In 6 hours interval dosage regimen, the percentages of the time > 4× minimum inhibitory concentration (MIC) at specific 4×MIC of 2, 4, 6, and 8 μg/mL of imipenem were more than 40% of the dosing interval. But in the 8 hours interval dosage regimen, when the level was above the 4×MIC of 4 μg/mL, maintaining time would drop below 40% of the dosing interval, with significant differences compared with that in 6 hours interval dosage regimen [4×MIC = 2 μg/mL: (60.84±20.25)% vs. (94.01±12.46)%, t = 4.977, P = 0.001; 4×MIC = 4 μg/mL: (39.85±15.88)% vs. (68.74±9.57)%, t = 5.562, P = 0.000; 4×MIC = 6 g/mL: (27.58±13.70)% vs. (53.97±8.36)%, t = 5.867, P = 0.000; 4×MIC = 8 μg/mL: ( 8.87±12.43)% vs. (43.48±7.83)%, t = 5.976, P = 0.000]. No significant change in sieving coefficient of imipenem was found within a short time (6 hours), which indicated that there was no effect of anticoagulation on clearance of imipenem by AN69-M100 filter, and no statistical significance was found with repeated measure analysis (F = 0.186, P > 0.05 ). The clearance rate of imipenem is increased significantly in vitro under the mode of CVVH with the actual dose of replacement fluid was (31.63±1.48) mL×kg⁻¹×h⁻¹ in severe infective patients with severe sepsis complicating AKI, affecting the level of plasma drug concentration, need to adjust the dosage regimen. When the time of the dosing interval was shortened, the concentration of imipenem in patients' plasma could be increased significantly. In a short period of time, the sieving coefficient of imipenem through AN69 filter is not affected by anticoagulation measures and time cleaning efficiency will not decline.

Pharmacokinetical Interactions of Amoxicillin and Amprolium in Broiler Chickens.

Bioavailability of amoxicillin following a single intravenous and oral administrations as well as tissue residues were determined in broiler chickens. Effect of amprolium on the disposition kinetics and tissue residues of amoxicillin following repeated oral administrations was also investigated. Following a single intravenous injection of amoxicillin, 20 mg/kg.b.wt., in normal broiler chickens , plasma concentration-time curve was best described by a three-compartments open model with elimination half-life t0.5 = 9.78 ± 0.43 h, volume of distribution Vdss=1012.06 ml/kg and total clearance of the drug CLtot =0.090 ml/kg/min. Following a single oral dosing, the maximum plasma concentration was 12.54 ± 0.140 g/ml, reached at Tmax =1.05 ± 0.042 h. The mean systemic bioavailability following oral administration was 67.33%. Following repeated oral administration in normal chickens, highest plasma concentration peaked after one hour of each oral dose. Amoxicillin showed accumulative behavior in plasma of broiler chickens. Amprolium resulted in a significant decrease in maximum plasma concentration of amoxicillin C max = 12.36 ± 0.506 g/ml compared with amoxicillin alone C max = 14.38 ± 0.373 g/ml. Amprolium resulted in a significant increase in total drug clearance Cltot = 1.43 ± 0.089 L/kg compared with amoxicillin alone (Cltot = 1.20 ± 0.028 L/kg). Amprolium resulted in a significant decrease in amoxicillin residues concentrations in all assayed tissues. It is concluded that the administration of amprolium before amoxicillin would altered its pharmacokinetic profile.

On the Accuracy of a One-Compartment Approach for Determination of Drug Terminal Half-Life

The drug terminal half-life (t(1/2)) is commonly predicted by a simplified one-compartment approach (t(1/2) = ln 2V(ss)/CL), where V(ss) and CL are the steady-state volume of distribution and the total body clearance of drug, respectively. The analysis of the accuracy of this approach is provided. It turns out that most often a simplified one-compartment calculation underestimates t(1/2) by no more than 25% for human, 26% for dog, 20% for monkey, 19% for rat, and 23% for mouse. Thus, the application of a one-compartment calculation of t(1/2) is well justifiable, except for the rare cases of very high drug clearance (CL/(rQ) ≳ 0.5), where r is the equilibrium blood-plasma concentration ratio, and Q is the cardiac output.

Which Metabolites Circulate?

Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (fm). Our analysis suggests that fm is the major determinant of total drug M/P ratio for amine, alcohol, N- and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with fm due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite.