Average Steady-state Concentration Research Articles

Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency-Guided First-in-Human Studies.

Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP‐ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady‐state concentration (Css) at the approved dose was compared to the in vitro cell potency (half‐maximal inhibitory concentration (IC50)). Average steady‐state area under the plasma concentration‐time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer‐reviewed journal articles. The Css was remarkably similar to the IC50. The median Css/IC50 value was 1.2, and 76% of the values were within 3‐fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a Css/IC50 value > 25. Seven other therapies targeting the same 3 kinases had much lower Css/IC50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first‐in‐human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and Css exceeds a potency threshold. This potency‐guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.

Clinical Pharmacokinetics of Fosfomycin after Continuous Infusion Compared with Intermittent Infusion: a Randomized Crossover Study in Healthy Volunteers.

Continuous infusion (CON) of fosfomycin has been proposed as potentially advantageous in certain clinical scenarios. However, no clinical data on the pharmacokinetics (PK) of fosfomycin after CON are available to date. This study aimed to investigate the PK of fosfomycin after CON and compare it with intermittent infusion (INT) of fosfomycin. A randomized two-way crossover study including 8 healthy male volunteers was performed. Each subject received fosfomycin as INT of 8 g over 30 min every 8 h and, separated by a washout period, as CON of 1 g/h preceded by a loading dose of 8 g over 30 min. PK sampling was performed for 18 and 24 h in the CON and INT groups, respectively. Fosfomycin was generally well tolerated. However, 2 out of 8 subjects (25%) developed thrombophlebitis at the infusion site following CON, which was prevented in the following subjects with a simultaneous coinfusion of Ringer's lactate. The steady-state maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h at steady state (AUCSS,0-24) of fosfomycin after INT were 551.5 ± 67.8 mg/liter and 3,678.5 ± 601.9 h · mg/liter, respectively. CON led to an average steady-state concentration of 183.8 ± 35.9 mg/liter, resulting in a calculated AUCSS,0-24 of 4,411.2 ± 862.4 h · mg/liter, which was 1.2-fold higher than that with INT. CON resulted in a 100% T>MIC (time during which the drug concentration exceeds the MIC) for MICs of ≤128 mg/liter, whereas the %T>MIC for INT was only 44% for an MIC of 128 mg/liter. CON of fosfomycin led to improved PK and PK/pharmacodynamic (PD) determinants in plasma of healthy volunteers. The clinical relevance of these findings remains to be investigated in patients.

Physiologically Based Pharmacokinetic Modeling of Central Nervous System Pharmacokinetics of CDK4/6 Inhibitors to Guide Selection of Drug and Dosing Regimen for Brain Cancer Treatment.

A better understanding of the human central nervous system (CNS) pharmacokinetics is critical to the selection of the right drug and refinement of dosing regimen for more effective treatment of primary and metastatic brain cancer. Using the physiologically‐based pharmacokinetic (PBPK) modeling approach, we systematically compared the CNS pharmacokinetics of three cyclin D‐cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors (ribociclib, palbociclib, and abemaciclib) in patients with cancer. A PBPK model platform was developed and verified for predicting plasma and CNS pharmacokinetics. Target engagement ratio (TER), defined as the ratio of the average steady‐state unbound drug brain concentration to the in vitro half‐maximal inhibitory concentration (IC50) for CDK4/6 inhibition, was used as a crude predictor of efficacy. As compared with ribociclib and palbociclib, abemaciclib penetrated into the human brain to a larger extent, but at a slower rate, and was retained in the brain longer. Following the standard dosing regimens, the predicted CDK4/6 TERs were 26/5.2 for abemaciclib, 2.4/0.62 for ribociclib, and 0.36/0.27 for palbociclib. Simulations suggested that abemaciclib achieved comparable TERs following twice daily or daily dosing; ribociclib may sufficiently inhibit both CDK4 and CDK6 at the maximum tolerated dose; whereas, palbociclib achieved TERs < 0.5 even at a dose 50% higher than the standard dose. In conclusion, the PBPK modeling, supported by available preclinical and clinical evidence, suggests that abemaciclib is the best CDK4/6 inhibitor for brain cancer treatment, whereas palbociclib is not recommended. The model refined dosing regimen is 300 mg daily on a 4‐weeks‐on schedule for abemaciclib, and 900 mg daily on a 3‐weeks‐on/1‐week‐off schedule for ribociclib.

Pharmacokinetics and safety of posaconazole intravenous solution and powder for oral suspension in children with neutropenia: an open-label, sequential dose-escalation trial

Posaconazole is approved for use in adults as an intravenous (IV) solution and two different oral formulations (a suspension and an improved bioavailability tablet). Data on the pharmacokinetics (PK), dosing and safety of posaconazole in children are limited. A novel powder for oral suspension (PFS) offers the bioavailability of the tablet formulated for weight-based dosing in children. A non-randomised, open-label, sequential dose-escalation, phase 1b trial evaluated the PK and safety of posaconazole IV and PFS in children aged 2 to 17 years with documented or expected neutropenia (ClinicalTrials.gov, NCT02452034; MSD protocol number, MK-5592-P097). Participants received posaconazole IV 3.5, 4.5 or 6.0 mg/kg/d for ≥10 days, with an option to switch to posaconazole PFS at the identical dose for ≤18 days. The target exposure was a mean within-dose cohort average steady-state plasma concentration (Cavg) of ~1200 ng/mL, with ~90% of participants achieving Cavg between 500 and 2500 ng/mL. Doses of 4.5 and 6.0 mg/kg/d achieved the PK target of ~90% of participants with a Cavg ≥500 ng/mL. PFS resulted in lower posaconazole exposures than IV across age groups at all doses. Posaconazole IV and PFS were well tolerated and had safety profiles similar to those reported for adults. Posaconazole PK following IV and PFS administration was well characterised by the data and enable selection of appropriate paediatric doses. Both formulations were well tolerated without dose-, exposure- or age-related differences in the safety profiles.

Platelet Inhibition With IV Glycoprotein IIb/IIIa Inhibitor to Prevent Thrombosis in Pediatric Patients Undergoing Aortopulmonary Shunting.

Shunt thrombosis, a potential complication of aortopulmonary shunting, is associated with high mortality. Commonly used oral antiplatelet drugs such as aspirin demonstrate variable absorption and inconsistent antiplatelet effect in critically ill patients early after surgery. IV glycoprotein IIb/IIIa inhibitors are antiplatelet agents with rapid and reproducible effect that may be beneficial as a bridge to oral therapy. Retrospective review of pediatric patients undergoing treatment with IV tirofiban. Discarded blood samples were used to determine pharmacokinetic parameters. Pediatric cardiac ICU at a single institution. Fifty-two pediatric patients (< 18 yr) undergoing surgical aortopulmonary shunt procedure who received tirofiban infusion as a bridge to oral aspirin. None. Primary outcome measures were shunt thrombosis and bleeding events, whereas secondary outcomes included measurement of platelet inhibition by thromboelastography with platelet mapping and pharmacokinetic analysis (performed in a subset of 15 patients). Shunt thrombosis occurred in two of 52 patients (3.9%) after prophylaxis treatment with tirofiban; both thrombosis events occurred after discontinuation of the drug. One patient (1.9%) experienced bleeding complication during the infusion. A tirofiban bolus of 10 µg/kg and infusion of 0.15 µg/kg/min resulted in significantly increased platelet inhibition via adenosine diphosphate pathway (median 66% [43-96] pre-tirofiban compared with 97% [92-99%] at 2 hr; p < 0.05). Half-life of tirofiban in plasma was 142 ± 1.5 minutes, and the average steady-state concentration was 112 ± 62 ng/mL. Age and serum creatinine were significant covariates associated with systemic clearance. Dosing simulations were generated based upon one compartment model. IV glycoprotein IIb/IIIa inhibitor as a bridge to oral antiplatelet therapy is safe in pediatric patients after aortopulmonary shunting. Dosing considerations should include both age and renal function. Randomized trials are warranted to establish efficacy compared with current anticoagulation practices.

Pharmacokinetics and pharmacodynamics in extracorporeal renal replacement therapy

Intermittent hemodialysis, continuous hemofiltration and prolonged daily dialysis are used for renal replacement therapy in the intensive care units. Independent of the replacement modality, antibiotic therapy must start with ahigh loading dose. Dose adjustment to the kidneys must follow 48 h later to prevent toxic accumulation. Dose recommendations on product labels are often underdosed. On continuous hemofiltration, meanwhile many intensivists administer anormal standard dose because the high filtration rate corresponds to ahalf-normal glomerular filtration rate. After intermittent hemodialysis, adose similar to the loading dose will be needed. On day off dialysis, the maintenance dose must be adjusted to the failing kidney function. Immediately after prolonged daily dialysis, aloading dose should be given; with twice daily dosing the maintenance dose needs to be adjusted to kidney function. Therapeutic drug monitoring is recommended for gentamicin, vancomycin, piperacillin, meropenem and voriconazole. Due to pharmacodynamic reasons, the target concentration corresponds to the concentration producing the half-maximum effect. Accordingly, the target concentration is the normal peak for concentration-dependent action with bolus dosing. The target is the average steady-state concentration for antibiotics with time-dependent action and continuous infusion.

The safety and pharmacokinetics of metformin in patients with chronic liver disease

The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n=34), and by a prospective study where metformin (500mg, immediate release, twice daily) for up to 6weeks was prescribed (n=24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5mg/L; lactate, 5mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P<0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P=0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CLMet /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P=0.03). The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145).

Sanguinarine metabolism and pharmacokinetics study in vitro and in vivo.

Sanguinarine (SA) is a benzo[c] phenanthridine alkaloid which has a variety of pharmacological properties. However, very little was known about the pharmacokinetics of SA and its metabolite dihydrosanguinarine (DHSA) in pigs. The purpose of this work was to study the intestinal metabolism of SA in vitro and in vivo. Reductive metabolite DHSA was detected during incubation of SA with intestinal mucosa microsomes, cytosol, and gut flora. After oral (p.o.) administration of SA, the result showed SA might be reduced to DHSA in pig intestine. After i.m. administration, SA and DHSA rapidly increased to reach their peak concentrations (Cmax , 30.16±5.85, 5.61±0.73ng/ml, respectively) at 0.25hr. Both compounds were completely eliminated from the plasma after 24hr. After single oral administration, SA and DHSA rapidly increased to reach their Cmax (3.41±0.36, 2.41±0.24ng/ml, respectively) at 2.75±0.27hr. The half-life (T1/2 ) values were 2.33±0.11hr and 2.20±0.12hr for SA and DHSA, respectively. After multiple oral administration, the average steady-state concentrations (Css ) of SA and DHSA were 3.03±0.39 and 1.42±0.20ng/ml. The accumulation indexes for SA and DHSA were 1.21 and 1.11. The work reported here provides important information on the metabolism sites and pharmacokinetic character of SA. It explains the reasons for low toxicity of SA, which is useful for the evaluation of its performance.

Exposure–response analysis of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia: pooled results from a phase 1b study and the phase 3 MURANO study

Exposure–response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (CmeanSS,nominal) for tolerability; exposure–safety analyses used logistic regression. Exposure–progression-free survival (PFS) relationships were assessed using MURANO data, with CmeanSS,nominal as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

In Vitro Activity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin against Pseudomonas aeruginosa.

Relebactam is a novel class A/C β-lactamase inhibitor that restores imipenem in vitro activity against multidrug-resistant and carbapenem-nonsusceptible Pseudomonas aeruginosa Time-kill analyses were performed to evaluate the potential role of imipenem-relebactam in combination with amikacin or colistin against P. aeruginosa Ten clinical P. aeruginosa isolates (9 imipenem nonsusceptible) with imipenem-relebactam MICs ranging from 1/4 to 8/4 μg/ml were included. The isolates had varied susceptibilities to imipenem (1 to 32 μg/ml), amikacin (4 to 128 μg/ml), and colistin (0.5 to 1 μg/ml). Duplicate 24-h time-kill studies were conducted using the average steady-state concentrations (Cssavg) observed after the administration of imipenem-relebactam at 500 mg/250 mg every 6 hours (q6h) alone and in combination with the Cssavg of 25 mg/kg of body weight/day amikacin and 360 mg/day colistin in humans. Imipenem-relebactam alone resulted in 24-h bacterial densities of -2.93 ± 0.38, -1.67 ± 0.29, +0.38 ± 0.96, and +0.15 ± 0.65 log10 CFU/ml at imipenem-relebactam MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. No synergy was demonstrated against the single imipenem-susceptible isolate. Against the imipenem-nonsusceptible isolates (n = 9), imipenem-relebactam combined with amikacin resulted in synergy (-2.61 ± 1.50 log10 CFU/ml) against all amikacin-susceptible isolates and in two of three amikacin-intermediate (i.e., MIC, 32 μg/ml) isolates (-2.06 ± 0.19 log10 CFU/ml). Synergy with amikacin was not observed when the amikacin MIC was >32 μg/ml. Imipenem-relebactam combined with colistin demonstrated synergy in eight out of the nine imipenem-resistant isolates (-3.17 ± 1.00 log10 CFU/ml). Against these 10 P. aeruginosa isolates, imipenem-relebactam combined with either amikacin or colistin resulted in synergistic activity against the majority of strains. Further studies evaluating combination therapy with imipenem-relebactam are warranted.

Analytical Solution and Exposure Analysis of a Pharmacokinetic Model with Simultaneous Elimination Pathways and Endogenous Production: The Case of Multiple Dosing Administration.

In this paper, a typical pharmacokinetic (PK) model is studied for the case of multiple intravenous bolus-dose administration. This model, of one-compartment structure, not only exhibits simultaneous first-order and Michaelis-Menten elimination, but also involves a constant endogenous production. For the PK characterization of the model, we have established the closed-form solution of concentrations over time, the existence and local stability of the steady state. Using analytical approaches and the concept of corrected concentration, we have shown that the area under the curve ([Formula: see text]) at steady state is higher compared to that at the single dose ([Formula: see text]). Moreover, by splitting the dose and dosing interval into halves, we have revealed that it can result in a significant decrease in the steady-state average concentration. These model-based findings, which contrast with the current knowledge for linear PK, confirm the necessity to revisit drugs exhibiting nonlinear PK and to suggest a rational way of using mathematical analysis for the dosing regimen design.

Polymyxin resistance in Klebsiella pneumoniae: multifaceted mechanisms utilized in the presence and absence of the plasmid-encoded phosphoethanolamine transferase gene mcr-1

Until plasmid-mediated mcr-1 was discovered, it was believed that polymyxin resistance in Gram-negative bacteria was mainly mediated by the chromosomally-encoded EptA and ArnT, which modify lipid A with phosphoethanolamine (pEtN) and 4-amino-4-deoxy-l-arabinose (l-Ara4N), respectively. This study aimed to construct a markerless mcr-1 deletion mutant in Klebsiella pneumoniae, validate a reliable reference gene for reverse transcription quantitative PCR (RT-qPCR) and investigate the interactions among mcr-1, arnT and eptA, in response to polymyxin treatments using pharmacokinetics/pharmacodynamics (PK/PD). An isogenic markerless mcr-1 deletion mutant (II-503Δmcr-1) was generated from a clinical K. pneumoniae II-503 isolate. The efficacy of different polymyxin B dosage regimens was examined using an in vitro one-compartment PK/PD model and polymyxin resistance was assessed using population analysis profiles. The expression of mcr-1, eptA and arnT was examined using RT-qPCR with a reference gene pepQ, and lipid A was profiled using LC-MS. In vivo polymyxin B efficacy was investigated in a mouse thigh infection model. In K. pneumoniae II-503, mcr-1 was constitutively expressed, irrespective of polymyxin exposure. Against II-503Δmcr-1, an initial bactericidal effect was observed within 4 h with polymyxin B at average steady-state concentrations of 1 and 3 mg/L, mimicking patient PK. However, substantial regrowth and concomitantly increased expression of eptA and arnT were detected. Predominant l-Ara4N-modified lipid A species were detected in II-503Δmcr-1 following polymyxin B treatment. This is the first study demonstrating a unique markerless deletion of mcr-1 in a clinical polymyxin-resistant K. pneumoniae. The current polymyxin B dosage regimens are suboptimal against K. pneumoniae, regardless of mcr, and can lead to the emergence of resistance.

Reactive Oxygen Species Production from Secondary Organic Aerosols: The Importance of Singlet Oxygen.

Organic aerosols are subjected to atmospheric processes driven by sunlight, including the production of reactive oxygen species (ROS) capable of transforming their physicochemical properties. In this study, secondary organic aerosols (SOA) generated from aromatic precursors were found to sensitize singlet oxygen (1O2), an arguably underappreciated atmospheric ROS. Specifically, we quantified 1O2, OH radical, and H2O2 quantum yields within photoirradiated solutions of laboratory-generated SOA from toluene, biphenyl, naphthalene, and 1,8-dimethylnaphthalene. At 5 mgC L-1 of SOA extracts, the average steady-state concentrations of 1O2 and of OH radicals in irradiated solutions were 3 ± 1 × 10-14 M and 3.6 ± 0.9 × 10-17 M, respectively. Furthermore, ROS quantum yields of irradiated ambient PM10 extracts were comparable to those from laboratory-generated SOA, suggesting a similarity in ROS production from both types of samples. Finally, by using our measured ROS concentrations, we predict that certain organic compounds found in aerosols, such as amino acids, organo-nitrogen compounds, and phenolic compounds have shortened lifetimes by more than a factor of 2 when 1O2 is considered as an additional sink. Overall, our findings highlight the importance of SOA as a source of 1O2 and its potential as a competitive ROS species in photooxidation processes.

Nomogram based on actual body weight for estimation of vancomycin maintenance dose in infants

Background: Vancomycin is the first-choice antibiotic for infants with β-lactam-resistant gram-positive bacterial infection. Despite long experience of prescribing of this drug optimal dosing is still challenging. This study aimed at investigating variables predicting vancomycin clearance in order to propose optimal maintenance dosing in infants treated for suspected or culture-proven sepsis.Methods: Vancomycin pharmacokinetics was calculated in a one-compartmental model based on serum concentrations. A linear regression model was used to explore relationships between vancomycin clearance and expected covariates.Results: Twenty-two patients were enrolled into the study. Median (IQR) postnatal age was 157 (112–238) days. The median (IQR) volume of distribution and clearance for vancomycin were 0.50 (0.39–0.94) L/kg and 0.112 (0.095–0.133) L/h/kg, respectively. Vancomycin clearance was associated with actual body weight, height, body surface area, gestational age, postnatal age, postmenstrual age and estimate glomerular filtration rate. Actual body weight was the best predictive variable for vancomycin clearance. Daily maintenance dose (mg) calculated as 76.28 × actual body weight (kg) – 41.57 most closely approximated optimal dosing based on individual pharmacokinetics. This relationship was used to construct a dosing nomogram.Conclusions: We developed an easy-to-use dosing nomogram for maintaining a vancomycin average steady-state concentration of 22.5 mg/L based on actual body weight.

850: Evaluation of breast milk concentrations following brexanolone iv administration to healthy lactating women

Brexanolone iv, a proprietary, intravenous formulation of allopregnanolone, is an investigational positive allosteric modulator of GABAA receptors and is under FDA review for the treatment of postpartum depression. The brexanolone iv dose regimen yields plasma concentrations of allopregnanolone that approximate endogenous levels at the end of pregnancy. We evaluated concentrations of allopregnanolone in breast milk and plasma for 7 days after the start of brexanolone iv infusion. This open-label, Phase 1b trial enrolled 12 healthy, lactating women, who were ≤6 months postpartum. Subjects received a 60-hour brexanolone iv infusion, titrated to a maximum of 90 μg/kg/h, as inpatients and were followed through Day 7. Breast milk was collected ad libitum at least every 12 hours through Day 7. Milk samples were retained for analysis. Expressed milk was not given to infants during the study. Plasma and breast milk were analyzed for allopregnanolone concentrations. Brexanolone iv safety and tolerability were monitored throughout the study. Plasma concentrations of allopregnanolone increased during dose titration and declined during dose taper, with an average steady state concentration (Cavg) of 70.56 ng/mL (95% CI 61.8-80.4), a t1/2 of 11.3 hours (95% CI 9.8- 13.1), and an area under the curve to infinity (AUC∞) of 3736.5 ng·h/mL (95% CI 3309.1-4219.1). Breast milk concentrations of allopregnanolone followed a similar pattern and fell below the limit of detection (5 ng/mL) in the majority of the women by approximately 3 days after infusion cessation. Overall pharmacokinetics results showed a rapid equilibrium between milk and plasma. The milk to plasma ratio appeared to be constant over a large range of plasma concentrations, with varying volumes of milk expressed and across subjects. There were no deaths, serious or severe adverse events, or clinically significant changes in safety tests, including laboratory results. Allopregnanolone concentrations were detected in breast milk of women receiving brexanolone iv. Concentrations in milk followed plasma concentrations closely, with rapid decline after the end of the 60-hour infusion to undetectable levels 3 days after the end of the infusion. There was no apparent accumulation of allopregnanolone in plasma or breast milk.

Association of CYP2D6 polymorphisms and extrapyramidal symptoms in schizophrenia patients receiving risperidone: a retrospective study

BackgroundRisperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy.MethodsSchizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs).ResultsA total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0–6.0) vs. 4.0 (2.0–7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5–6.5) vs. 0.0 (0.0–3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05).ConclusionSpecial attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.

Is Extraterrestrial Life Suppressed on Subsurface Ocean Worlds due to the Paucity of Bioessential Elements?

Abstract The availability of bioessential elements for “life as we know it”, such as phosphorus (P) or possibly molybdenum (Mo), is expected to restrict the biological productivity of extraterrestrial biospheres. Here, we consider worlds with subsurface oceans and model the dissolved concentrations of bioessential elements. In particular, we focus on the sources and sinks of P (available as phosphates) and find that the average steady-state oceanic concentration of P is likely to be lower than the corresponding value on Earth by a few orders of magnitude, provided that the oceans are alkaline and possess hydrothermal activity. While our result does not eliminate the prospects of life on subsurface worlds like Enceladus, it suggests that the putative biospheres might be oligotrophic and perhaps harder to detect. Along these lines, potential biospheres in the clouds of Venus may end up being limited by the availability of Mo. We also point out the possibility that stellar spectroscopy can be used to deduce potential constraints on the availability of bioessential elements on planets and moons.

Pharmacokinetics of Single-Dose Oral Pregabalin Administration in Normal Cats.

Objective: To describe the pharmacokinetic parameters of oral pregabalin in normal cats after single oral dosing.Animals: Six healthy adult research cats.Procedures: Following sedation and indwelling catheter placement, one oral (4 mg/kg) dose of pregabalin was administered. Blood samples were collected at 0, 15 and 30 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 h after administration. Plasma pregabalin concentrations were measured by high-performance liquid chromatography and subjected to pharmacokinetic analysis using commercial software.Results: Four of six cats developed moderate sedation after pregabalin administration. The peak pregabalin concentration was 8.3 ± 1.6 μg/ml which occurred at 2.9 ± 1.2 h. Elimination half-life was 10.4 ± 2.6 h and area under the curve was 133.9 ± 71.5 μg-h/ml. Time above the minimum therapeutic concentration for seizure control in dogs and people (2.8 μg/ml) was 17.6 ± 6.2 h. Using these data, predicted minimum, maximum and average steady state concentrations were calculated for 12 and 24 h dosing intervals.Conclusions and Clinical Relevance: Pregabalin (4 mg/kg) administered orally to cats results in plasma concentrations within the range considered to be efficacious for seizure control in dogs and humans between 1.5 and at least 12 h. Because of moderate sedative side effects in the majority of cats at this dose and high calculated maximum steady state concentrations, a lower dose, given more frequently (1–2 mg/kg q 12 h), should be evaluated in prospective clinical studies.

Diverse genetic alterations responsible for post-exposure colistin resistance in populations of the same strain of Klebsiella pneumoniae

The intra- and interstrain diversity of genetic alterations in Klebsiella pneumoniae after exposure to colistin was investigated. Four colistin-susceptible K. pneumoniae strains with different sequence types were exposed to 2 mg/L colistin, the average steady-state plasma concentration. After exposure, 10 single-step colistin-resistant mutants were selected in vitro from each K. pneumoniae strain. Minimum inhibitory concentrations (MICs) were evaluated by broth microdilution. Nucleotide sequences of genes associated with colistin resistance (phoPQ, pmrAB, mgrB and crrAB) were determined, and the mRNA expression levels of pbgP, phoP, phoQ, pmrD, pmrA and pmrB were measured by quantitative real-time polymerase chain reaction. Colistin MICs for single-step mutants ranged from 4 to >64 mg/L. Diverse amino acid alterations in pmrB, phoP, phoQ and mgrB, including insertion sequences, were identified in the colistin-resistant mutants. Different mutations were found even among mutants originating from the same parental strain, and several mutants displayed no mutations in the tested genes. While most colistin-resistant mutants showed elevated expression of pbgP, seven showed no increase compared with their susceptible parental strain, and some mutants exhibited no overexpression of pmrAB, phoPQ or pbgP. These results demonstrate the diversity of genetic variations in colistin-resistant populations derived from the same parental strain, and suggest that there are still unknown mechanisms of colistin resistance in K. pneumoniae.

Population exposure\u2013response analysis of cabozantinib efficacy and safety endpoints in patients with renal cell carcinoma

BackgroundIn the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx™) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure.Objectives and methodsExposure–response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints.ResultsCompared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (− 11.9 vs − 9.1 and − 4.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (grade ≥ 1), fatigue/asthenia (grade ≥ 3), diarrhea (grade ≥ 3), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose.ConclusionER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs.