Steady-state Peak Concentrations Research Articles

Comparison of Vancomycin AUC24 Calculation Methods for Neonates and Infants.

For neonates and infants receiving intermittent vancomycin infusions, the area under the concentration-timecurve during 24 h (AUC24) is often estimated with Bayesian forecasting using one or more measured vancomycin concentrations. When practical peak and trough concentrations are measured at steady state, AUC24 can also be calculated with first-order steady-state equations for a one-compartment model (Sawchuk-Zaske method), but previously this method has been applied only for adults. The objective of this studywas to compare AUC24 values obtained with the Sawchuk-Zaske method and two Bayesian models. AUC24 values were estimated retrospectively for 18 neonates and infants with steady-state peak and trough concentrations using traditional compartmental analysis with a one-compartment model (reference method), the Sawchuk-Zaske method, and Bayesian forecasting with two previously published models. In Bayesian forecasting, both original and modified residual error models were used. In the modified models, the residual error was reduced by setting the additive residual error to zero and the proportional error to 15%. AUC24 estimates obtained with the Sawchuk-Zaske method differed -2.7 to 0.9% from the reference method. When both peak and trough concentrations were used in Bayesian forecasting, 61% and 33% of AUC24 estimates obtained with two original models differed less than 15% from the reference method, and these fractions increased to 83% and 72% with the modified models, respectively. When practical peak and trough concentrations are measured at steady state, the simple Sawchuk-Zaske method is very useful for AUC24 estimation in neonates and infants. In Bayesian forecasting, the reduced residual error model can be used to improve the model fit.

Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations

Levetiracetam may cause acute renal failure and myoclonic encephalopathy at high plasma levels, particularly in patients with renal impairment. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict levetiracetam pharmacokinetics in Chinese adults with epilepsy and renal impairment and define appropriate levetiracetam dosing regimen.PBPK models for healthy subjects and epilepsy patients with renal impairment were developed, validated, and adapted. Furthermore, we predicted the steady-state trough and peak concentrations of levetiracetam in patients with renal impairment using the final PBPK model, thereby recommending appropriate levetiracetam dosing regimens for different renal function stages. The predicted maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration–time curve (AUC) were in agreement (0.8 ≤ fold error ≤ 1.2) with the observed, and the fold error of the trough concentrations in end-stage renal disease (ESRD) was 0.77 − 1.22. The prediction simulations indicated that the recommended doses of 1000, 750, 500, and 500 mg twice daily for epilepsy patients with mild, moderate, severe renal impairment, and ESRD, respectively, were sufficient to achieve the target plasma concentration of levetiracetam.

Population Pharmacokinetics of Atorvastatin in High-Altitude and Plain Patients with Hyperlipidemic.

The pharmacokinetic (PK) characteristics of drugs were altered under high-altitude hypoxia. We aim to describe the population PK of atorvastatin (ATV) to identify patient characteristics that are predictive of variability in the PK parameters of the ATV and investigate the effects of high-altitude hypoxia on the blood concentration of ATV in patients with hyperlipidemia. A total of 160 plasma concentrations were collected from 40 patients with hyperlipidemia in plateau areas and 40 in plain areas. The population pharmacokinetic model of patients with hyperlipidemia in plateau and plain areas of China was established by a nonlinear mixed-effects model. The PK of ATV were described by a 1-compartment model with first-order elimination. The main PK parameters of ATV were the first-order absorption rate (0.76hour-1 fixed); clearance (174.22L/h) and apparent volume of distribution (1119.62L). The values of area and age were identified as significant covariates for the clearance, area, age, and urea for the volume of distribution. The steady-state peak concentration in the plateau area was higher than that in the plain area. This study may suggest dose reduction is necessary for patients with hyperlipidemia in high altitudes.

Sub-therapeutic trimethoprim and sulfamethoxazole plasma concentrations during continuous venovenous hemofiltration in a patient with COVID-19 and pulmonary Pneumocystis jirovecii co-infection: Acase report.

To investigate drug concentration of trimethoprim-sulfamethoxazole (TMP-SMX) using therapeutic drug monitoring (TDM) for severe Pneumocystis jirovecii (PJP) infection in a critically ill patient with COVID-19 receiving continuous venovenous hemofiltration treatment and regional citrate anticoagulation (RCA-CCVH). A 72-year-old man with hypoxemic respiratory failure due to COVID-19 infection was admitted to the intensive care unit for invasive mechanical ventilation. The patient developed acute renal failure that required RCA-CVVH. Pulmonary co-infection with PJP was diagnosed, and a high TMP-SMX dose was initiated according to (inter)national guidelines with dose reduction after 3 days because of renal failure. Population pharmacokinetics were assessed for TMP and SMX as well as clearance by RCA-CVVH, volume of distribution, and time above threshold levels for measured plasma concentrations. During renal failure requiring RCA-CVVH, a corresponding dose reduction of TMP-SMX to 320/1,600 mg twice a day, according to current Dutch SWAB and Dutch Association of Hospital Pharmacists guidelines, resulted in unintended under-dosing with sub-therapeutic TMP-SMX concentrations. Pharmacokinetic modeling and dose adjustment of TMP-SMX to 640/3,200 mg 3 times daily resulted in steady-state TMP-SMX peak concentrations associated with efficacy against PJP. Hence, the patient was successfully weaned from the ventilator and discharged. We hypothesize that our new dose recommendation of 640/3,200 mg TMP-SMX 3 times daily is associated with an increased probability of critical patients being successfully liberated from mechanical weaning following PJP pneumonia and COVID-19 infection.

Effect of continuous renal replacement therapy on plasma concentration, clinical efficacy and safety of colistin sulfate

To investigate the effects of continuous renal replacement therapy (CRRT) on plasma concentration, clinical efficacy and safety of colistin sulfate. Clinical data of patients received with colistin sulfate were retrospectively analyzed from our group's previous clinical registration study, which was a prospective, multicenter observation study on the efficacy and pharmacokinetic characteristics of colistin sulfate in patients with severe infection in intensive care unit (ICU). According to whether patients received blood purification treatment, they were divided into CRRT group and non-CRRT group. Baseline data (gender, age, whether complicated with diabetes, chronic nervous system disease, etc), general data (infection of pathogens and sites, steady-state trough concentration, steady-state peak concentration, clinical efficacy, 28-day all-cause mortality, etc) and adverse event (renal injury, nervous system, skin pigmentation, etc) were collected from the two groups. A total of 90 patients were enrolled, including 22 patients in the CRRT group and 68 patients in the non-CRRT group. (1) There was no significant difference in gender, age, basic diseases, liver function, infection of pathogens and sites, colistin sulfate dose between the two groups. Compared with the non-CRRT group, the acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) were higher in the CRRT group [APACHE II: 21.77±8.26 vs. 18.01±6.34, P < 0.05; SOFA: 8.5 (7.8, 11.0) vs. 6.0 (4.0, 9.0), P < 0.01], serum creatinine level was higher [μmol/L: 162.0 (119.5, 210.5) vs. 72.0 (52.0, 117.0), P < 0.01]. (2) Plasma concentration: there was no significant difference in steady-state trough concentration between CRRT group and non-CRRT group (mg/L: 0.58±0.30 vs. 0.64±0.25, P = 0.328), nor was there significant difference in steady-state peak concentration (mg/L: 1.02±0.37 vs. 1.18±0.45, P = 0.133). (3) Clinical efficacy: there was no significant difference in clinical response rate between CRRT group and non-CRRT group [68.2% (15/22) vs. 80.9% (55/68), P = 0.213]. (4) Safety: acute kidney injury occurred in 2 patients (2.9%) in the non-CRRT group. No obvious neurological symptoms and skin pigmentation were found in the two groups. CRRT had little effect on the elimination of colistin sulfate. Routine blood concentration monitoring (TDM) is warranted in patients received with CRRT.

Vancomycin AUC values estimated with trough-only data: Accuracy in an adult academic medical center population.

Vancomycin area under the concentration-time curve (AUC) can be calculated using steady-state serum peak and trough concentrations; however, compared to traditional trough-only monitoring, this approach requires an additional blood sample. Recently published data demonstrated vancomycin AUC estimations using trough-only data with a volume of distribution (Vd) model incorporating age and actual body weight were reasonably accurate and precise in a veteran population. This study sought to extend these methods to a Mayo Clinic adult population. A retrospective, observational cohort of adult patients with documented steady-state vancomycin peak and trough concentrations was evaluated. Vancomycin AUCs were estimated using trough-only data, and 4 Vd models were assessed for accuracy and precision. Estimated AUCs were compared to AUCs calculated using 1-compartment intermittent infusion equations and steady-state peak and trough ("peak-trough") data. The study population (N = 95) was 46% female, with a median age of 59 years and a median weight of 97 kg. Using the VancoPK equation Vd = 0.29 (age in y) + 0.33 (actual weight in kg) + 11, the mean peak-trough and estimated trough-only AUC were 533 and 534, respectively, with a correlation of 0.936. The root mean square error was 47.7, meaning about 95% of AUCs were within 95 mg · h/L of peak-trough AUCs. Accuracy and precision of Vancomycin AUC estimations using trough-only data and the described Vd model were demonstrated in a Mayo Clinic cohort. Targeting an estimated AUC of 500 mg · h/L using the VancoPK model would likely result in an actual AUC within 400 to 600 mg · h/L.

Comparison of Open-Access, Trough-Only Online Calculators Versus Trapezoidal Method for Calculation of Vancomycin Area Under the Curve (AUC).

Vancomycin area-under-the-curve (AUC) monitoring is associated with reduced nephrotoxicity but may increase cost and workload for personnel compared to trough monitoring. The purpose of this study was to compare the accuracy of vancomycin AUC calculated by open-access, online, trough-only calculators to AUCs calculated by the trapezoidal method (TM) using peak and trough concentrations. This retrospective, multi-center study included adults ≥18 years old with stable renal function who received vancomycin with steady-state peak and trough concentrations. Areas under the curve calculated by TM were compared to AUCs calculated by 3 online calculators using trough-only options for calculation: ClinCalc, VancoVanco, and VancoPK. The primary outcome was actual difference in AUC between TM and the online calculators. Secondary outcomes were percent difference in AUC and clinical alignment in dose adjustments between methods. Seventy patients were included for analysis. There was a statistically significant difference in AUC between TM and ClinCalc (median actual difference: -52, P < 0.001) and VancoVanco (median actual difference: 95, P < 0.001), whereas there was no significant difference between TM and VancoPK (median actual difference: -0.8, P = 0.827). Discordant dose adjustments were indicated when comparing ClinCalc, VancoVanco, and VancoPK to TM in 28%, 36%, and 12% of cases, respectively. The AUC calculator most closely aligned with TM was VancoPK, whereas other included calculators were statistically different. Owing to the cost and complexity of obtaining multiple levels, our findings support using a single steady-state trough using VancoPK as an alternative to TM for calculation of vancomycin AUC.

Effect of Isavuconazole on Plasma and CSF Levels of Ibrutinib and Plasma Levels of Liposomal Doxorubicin Among Patients Receiving Teddi-R for CNS Lymphoma

Background: Ibrutinib is an oral BTK inhibitor that is highly effective for B-cell lymphomas and chronic graft versus host disease. Escalating doses of ibrutinib were highly active and achieved good CNS penetration when added to temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) in primary CNS lymphoma (PCNSL) but was associated with aspergillosis (Lionakis Cancer Cell 2017). To prevent aspergillosis, we added the antifungal agent isavuconazole (isa) to the TEDDI-R regimen, but it is a moderate inhibitor of CYP3A4 and inhibits ibrutinib clearance. We performed a new dose escalation study of ibrutinib with concomitant isavuconazole and TEDD-R in PCNSL with a dose expansion cohort. In a separate study, we tested fixed doses of ibrutinib with TEDD-R in secondary CNS lymphoma (SCNSL) with pharmacokinetic (PK) sampling from plasma and cerebrospinal fluid (CSF). Herein we present the PK of ibrutinib in plasma and CSF from both ongoing studies along with plasma PK of liposomal doxorubicin. Methods: Patients with untreated and relapsed/refractory PCNSL enrolled onto the phase 1 trial of TEDDI-R with isa in a standard 3+3 fashion testing three dose levels of ibrutinib: DL1=280 mg, DL2=420 mg, and DL3=560 mg. Patients with untreated and relapsed/refractory SCNSL were enrolled onto a phase 2 trial of TEDDI-R with isa and a fixed dose of ibrutinib 560 mg. Isa was started ≥3 days before ibrutinib and continued throughout combination therapy of 4 to 6 cycles. At the first dose of ibrutinib, patients with PCNSL underwent plasma and CSF sampling at the following timepoints: pre-dose, then 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10-18 hr (one sample in this timeframe), and 24 hr post-dose. Patients with SCNSL underwent plasma sampling at pre-dose, 1 hr, and 10-18 hr (one sample in this timeframe) after the first ibrutinib dose. All patients also had steady-state (≥4 prior ibrutinib doses) plasma and CSF sampling at pre-dose and 2 hr post-dose. Plasma sampling for liposomal doxorubicin (dose range 30-50 mg/m2) occurred at pre-dose and at 5-8 hours post-dose. Concentrations were measured using LC-MS/MS (Frontage Laboratories and NCI). PK parameters were estimated using non-compartmental methods. Results: 55 consecutive patients (30 PCNSL, 25 SCNSL) were included for analysis. Among the 30 patients with dense first-dose sampling, the Tmax was 2.05 hr (SD 1.06, n=30), T1/2 8.3 hr (median 6.2 hr, SD 6.4, n=26), volume of distribution 13121 L (median 10756, SD 11422, n=24), and clearance 1560 L/hr (median 1093, SD 1397, n=24) (patients with r2<0.9 excluded). There was wide interpatient variability in ibrutinib PK. In both the plasma and CSF, ibrutinib 560 mg + isa had a higher AUC, Cmax, and steady-state peak concentration than 560 mg alone. Compared to 700 mg and 840 mg alone, 560 mg + isa had a similar AUC and Cmax in the plasma, but a higher steady-state peak plasma concentration. In the CSF, 560 mg + isa had a similar AUC and Cmax but higher steady-state peak concentration compared to 700 mg alone, and a higher AUC and Cmax but similar steady-state peak concentration compared to 840 mg alone (Tables 1 and 2). Peak (5-8 hours post-dose) plasma concentrations of liposomal doxorubicin were not significantly different with isa versus without isa (dose-normalized geometric mean ratio 0.94, 95% CI 0.80-1.08, n=82 data points). Conclusions: Isavuconazole increases the plasma and CSF exposure of ibrutinib approximately 2-fold, allowing for similar or improved CNS penetration at 560 mg compared to what was previously observed with ibrutinib 700 mg and 840 mg without isavuconazole. Further development of the TEDDI-R regimen utilizes ibrutinib 560 mg as the target dose along with isavuconazole. Plasma concentrations of liposomal doxorubicin were not significantly affected by isavuconazole. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Application Value of Pharmacokinetic Parameters of Vancomycin in Children Treated in the Pediatric Intensive Care Unit.

ObjectiveTo explore the efficacy and safety of vancomycin as measured by pharmacokinetic/pharmacodynamic parameters in children with severe infection in the Pediatric Intensive Care Unit (PICU) and to determine the appropriate threshold for avoiding nephrotoxicity.MethodsThe medical records of hospitalized children with severe infection treated with vancomycin in the PICU of a tertiary pediatric hospital from September 2018 to January 2021 were retrospectively collected. Univariate analysis was used to assess the correlation between vancomycin pharmacokinetic/pharmacodynamic parameters and therapeutic efficacy or vancomycin-related nephrotoxicity. Binary logistic regression was used to analyze the risk factors for vancomycin-related nephrotoxicity. The vancomycin area under the concentration-time curve over 24 h (AUC0–24) threshold was determined by receiver operating characteristic (ROC) curve analysis.ResultsOne hundred and 10 patients were included in this study. Seventy-six patients (69.1%) exhibited clinically effective response, while the rest exhibited clinically ineffective response. There were no significant differences in APACHE II score, steady-state trough concentration, peak concentration or AUC0–24 of vancomycin between the effective and ineffective groups. Among the 110 patients, vancomycin-related nephrotoxicity occurred in 15 patients (13.6%). Multivariate analysis showed that vancomycin treatment duration, trough concentration, and AUC0–24 were risk factors for vancomycin-related nephrotoxicity. The ROC curve indicated that AUC0–24 < 537.18 mg.h/L was a suitable cutoff point for predicting vancomycin-related nephrotoxicity.ConclusionNo significant correlations were found between the trough concentration or AUC0–24 of vancomycin and therapeutic efficacy when the daily dose of vancomycin was approximately 40 mg/kg d, while the trough concentration and AUC0–24 were both closely related to vancomycin-related nephrotoxicity. The combination of AUC0–24 and trough concentration for therapeutic drug monitoring may reduce the risk of nephrotoxicity.

Apixaban Concentrations in Routine Clinical Care of Older Adults With Nonvalvular Atrial Fibrillation

BackgroundDirect-acting oral anticoagulants are first-line agents for prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF), but data are limited for the oldest patients, and with reduced dosing. ObjectivesThe purpose of this study was to determine steady-state apixaban peak and trough concentrations during routine care of older adults with NVAF, compare concentrations to clinical trial concentrations, and explore factors associated with concentrations. MethodsA cross-sectional study of medically stable older adults with NVAF (age ≥75 years or ≥70 years if Black) receiving apixaban. Peak (2.0-4.4 hours post-dose) and trough (before next dose) concentrations were determined by anti-Xa activity calibrated chromogenic assay. Patient characteristics associated with concentrations were determined by multivariate modeling. ResultsThe median age of patients (n = 115) was 80 (interquartile range: 77-84) years. The cohort comprised 46 women and 69 men; of which 98 are White, 11 are Black, and 6 are Asian. With 5 mg twice daily per labelling (n = 88), peak concentrations were higher in women: 248 ± 105 vs 174 ± 67 ng/mL in men (P < 0.001) and exceeded expected 95% range in 6 of 30 vs 0 of 55 men (P = 0.002). With 2.5 mg twice daily per label (n = 11), concentrations were <5 mg twice daily (peak: 136 ± 87 vs 201 ± 90 ng/mL, P = 0.026; trough: 65 ± 28 vs 109 ± 56 ng/mL, P < 0.001), but not different than 2.5 mg twice daily without reduction criteria (n = 13; peak: 132 ± 88 ng/mL; trough: 65 ± 31 ng/mL). Covariates associated with concentrations included sex, number of daily medications, and creatinine clearance. ConclusionsOlder women had higher than expected peak apixaban concentrations, and 2.5 mg twice daily produced lower concentrations than standard dosing. Factors not currently included in dosing recommendations affected concentrations. The impact of apixaban concentrations on outcomes needs evaluation.

A Reevaluation of Prazosin Pharmacokinetics in a Two-Compartment Model, the Apparent Volume of Distribution and Comparative Simulations in the One-Compartment Model

Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.

Pharmacokinetics and Exposure-Response Relationship of Teprotumumab, an Insulin-Like Growth Factor-1 Receptor-Blocking Antibody, in Thyroid Eye Disease.

Background and ObjectiveThyroid eye disease (TED) is characterized by inflammation/expansion of orbital tissues, proptosis, and diplopia. Teprotumumab is the first US Food and Drug Administration-approved therapy for TED, administered as an initial intravenous infusion of 10 mg/kg followed by 20 mg/kg every 3 weeks for an additional seven infusions. The objective of this article is to discuss the pharmacokinetics and exposure-response profile for teprotumumab in patients with TED.MethodsA population pharmacokinetic analysis was performed to characterize pharmacokinetics and select dosing in patients with TED. Exposure-response was evaluated for efficacy (proptosis response, clinical activity score categorical response, and diplopia response) and safety (hyperglycemia, muscle spasms, and hearing impairment) parameters.ResultsTeprotumumab pharmacokinetics was linear in patients with TED, with low systemic clearance (0.334 L/day), low volume of distribution (3.9 and 4.2 L for the central and peripheral compartment, respectively), and a long elimination half-life (19.9 days). The approved dosing regimen provided > 20 µg/mL for > 90% insulin-like growth factor 1 receptor saturation throughout the dosing interval. Model-predicted mean (± standard deviation) steady-state area under the concentration-time curve, peak, and trough concentrations in patients with TED were 131 (± 30.9) mg∙h/mL, 643 (± 130) µg/mL, and 157 (± 50.6) µg/mL, respectively. Female patients had a 15% higher steady-state peak concentration but a similar steady-state area under the concentration-time curve vs male patients. No other covariates affected teprotumumab pharmacokinetics. No meaningful correlations between teprotumumab exposures and efficacy or safety parameters were observed.ConclusionsTeprotumumab pharmacokinetics was well characterized in patients with TED, and generally consistent with other IgG1 antibodies. Efficacy was consistent across the exposure range with a well-tolerated safety profile supporting the current dose regimen for patients with TED.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01003-3.

The Benefit of Therapeutic Drug Monitoring of Vancomycin in a Respiratory ICU; A Patient with Acute Kidney Injury: A Case Report

Introduction: Vancomycin damage to the kidney is one of the severe adverse reactions. The primary objective of this study was to discuss how the clinical pharmacists should deal with the results of therapeutic drug monitoring (TDM) for Vancomycin. Case Presentation: A case of severe acute kidney injury in a 60-year-old woman receiving Vancomycin as empirical therapy is reported here. The patient was admitted to the respiratory intensive care unit (RICU) of the First Affiliated Hospital of Bengbu Medical College, China, on 15 Oct 2015. On Day 7, the steady-state serum trough concentration and peak concentration of Vancomycin were 102.2 and 111.9 μg/mL, respectively. Clinical pharmacists immediately contacted the clinicians and advised them to discontinue Vancomycin therapy as soon as possible, and the proposal was adopted. On Day 8, serum creatinine (SCr) increased to 719 μmol/L, and creatinine clearance rate (CrCl) decreased to 6 mL/min; then, the patient was given dialysis treatment. After she underwent dialysis treatment, SCr decreased to 330 μmol/L and CrCl increased to 14 mL/min on Day 19; then, the patient was discharged after she accepted the doctor’s advice to start a home-dialysis program outside the hospital. Conclusions: In this case, clinical pharmacists contacted the doctor to avoid further aggravated renal damage timely when they found a significant increase in Vancomycin concentrations. It indicates that the Vancomycin level can be used as an indirect marker of renal function as increased Vancomycin level results from and contributes to acute kidney injury.

Abstract CT101: A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types

Abstract Introduction: The anti-PD-1 checkpoint inhibitor NIVO provides favorable safety and efficacy when administered at 3 mg/kg Q2W across multiple tumor types. Alternative dosing schedules would provide flexibility and offer benefits to patients and prescribers. A well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well characterized, relatively flat E-R relationships for efficacy and safety support the use of model-based approaches to qualify other potential NIVO doses and schedules. Methods: The feasibility of extending the dosing interval of NIVO from Q2W to Q4W was investigated using a combination of quantitative clinical pharmacology analyses and safety assessments. The predicted benefit-risk profile of NIVO 480 mg Q4W relative to 3 mg/kg Q2W was assessed by the following analyses: (1) comparison of NIVO exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types; (2) evaluation of NIVO exposure margins for safety relative to the well-tolerated dose of 10 mg/kg Q2W; (3) comparison of predicted risk of experiencing adverse events (Gr3+ AEs, immune-mediated AEs) with 480 mg Q4W relative to 3 mg/kg Q2W across indications of melanoma, NSCLC, RCC, UC, H&amp;N and cHL; and (4) comparison of predicted objective tumor response (OR) and overall survival with NIVO 480 mg Q4W relative to 3 mg/kg Q2W in patients with melanoma, NSCLC, and RCC. Results: Steady-state peak, time-averaged, and trough NIVO concentrations predicted with 480 mg Q4W were approximately 44% higher, 4% higher, and 18% lower, respectively, compared with 3 mg/kg Q2W. The aggregate of safety data accumulated for NIVO up to a dose level of 10 mg/kg Q2W in multiple tumor types provides a wide safety margin for the maximum concentration values expected with 480 mg Q4W. The steady-state exposures produced by 480 mg Q4W were lower than the corresponding exposures with 10 mg/kg Q2W, which has been shown to have acceptable safety and tolerability. The predicted probabilities of achieving an OR with NIVO 480 mg Q4W were similar to those with 3 mg/kg Q2W (&amp;lt;1% difference) across tumor types. Predicted 1- and 2-year survival probabilities were also similar to that of NIVO 3 mg/kg Q2W (differences ranging between 0%-4.6% at year 1, and 1.9%-6.9% at year 2) across tumor types. Conclusion: With a well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well-characterized E-R relationships for efficacy and safety, the differences in exposures produced by a NIVO schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule are not expected to result in clinically meaningful differences in the safety and efficacy of NIVO. The proposed 480 mg Q4W schedule has been incorporated into NIVO clinical trials (NCT02713867, NCT02714218) across multiple tumor types. Citation Format: Xiaochen Zhao, Vijay Ivaturi, Mathangi Gopalakrishnan, Jun Shen, Yan Feng, Paul Statkevich, Eric Richards, Michelle Rashford, Vicki Goodman, Joga Gobburu, Akintunde Bello, Amit Roy, Shruti Agrawal. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2017-CT101

A More Accurate Method to Estimate Aminoglycoside Clearance From Serum Creatinine in Patients With Spinal Cord Injury.

Background: Current literature reports that the traditional methods overestimate renal function in spinal cord injury (SCI); however, there is no accepted standard method. Objective: This study evaluated 6 published methods against measured aminoglycoside (AG) drug clearance and determined the frequency with which each method would achieve target peak and trough AG concentrations within a specified range. Methods: A chart-based investigation was conducted at a hospital with a large SCI population, and a total of 35 patients met the inclusion criteria: a diagnosis of long-standing SCI, administration of AG via intravenous infusion, and at least one set of steady-state AG peak and trough concentrations. Pharmacokinetic analysis was performed to compare the measured AG clearance values against the values resulting from 6 methods of estimating the glomerular filtration rate (GFR). Patient-specific pharmacokinetic parameters were used to simulate steady-state peak and trough AG concentrations from doses derived from each method. Results: Compared with the other methods, the Lee-Dang method was found to be more accurate, with the smallest magnitude of variance from the measured AG clearance values. Five alternative methods significantly overestimated AG clearance, by approximately 70% to 160% (P < .05). The Lee-Dang method underestimated AG clearance (by 10%), however not to a significant degree (P = .079). Compared with the alternative methods, the Lee-Dang method resulted in a higher frequency of steady-state peak and trough AG concentrations within the target range specified. Conclusion: The Lee-Dang equation for predicting GFR was more accurate relative to the other methods in the study population of patients with long-term SCI.

Phase I adult brain tumor consortium (ABTC) trial of ABT-888 (veliparib), temozolomide (TMZ), and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM) including pharmacokinetic (PK) data.

2065 Background: ABTC conducted a dose finding trial of ABT-888, an orally administered Poly(ADP-ribose) polymerase [PARP] inhibitor, during daily TMZ with post-operative RT for GBM. PARP is important in repair pathways for RT induced DNA injury and TMZ induced alkylation at N7-methylguanine and N3-methyldenine. Methods: An initial safety group (no concurrent RT), received ABT-888 10 mg BID po during 42 days of daily TMZ 75 mg/m2. After this, the planned dosing steps included ABT-888 BID concurrent with standard RT and TMZ, with planned ABT-888 dose escalation or de-escalation based on observed toxicity. Dose limiting toxicity (DLT) is ≥ grade 3 non-hematologic or neurologic not responding to steroids, and hematologic ANC&lt;500/mm3 and platelets (PLT) &lt; 25K/mm3. The pharmacokinetics (PK) of ABT-888 were characterized for dose 1 and at steady-state. Results: Without concurrent RT, DLT (thrombocytopenia) occurred in 1/6 patients. With concurrent RT/TMZ and ABT-888 10 mg BID, 4/12 patients had DLT (thrombocytopenia). As per the planned dose de-escalation, ABT-888 10 mg BID was then given every other week during TMZ/RT. This resulted in 3/6 patients with DLT (2 thrombocytopenia, 1 neutropenia). The hematologic toxicity with this regimen was judged high enough that accrual was discontinued. In the setting of continuous dosing for 6 weeks, the total body clearance of ABT-888 for the first dose (27.5±9.5 L/h, n = 15) and at steady-state after BID dosing (23.5±10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56±33%. Steady-state peak and trough concentrations of the drug in plasma were 66±29 ng/mL and 18±10 ng/mL, respectively. Additional PK data will be presented. Conclusions: Administering ABT-888 BID po in combination with standard RT/TMZ was not tolerable in GBM patients as a result of hematologic toxicity. ABT-888 PK in GBM patients were very similar to findings reported for solid tumor patients. There is strong scientific rationale for continued development of an appropriate dosing regimen for this agent in the initial therapy of GBM. Clinical trial information: NCT00770471.

The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model.

Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼10(6) and ∼10(8) CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [C(max)] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 10(6)-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 10(8)-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (C(max), 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.

Pharmacokinetics of panaxatrol disuccinate sodium, a novel anti-cancer drug from Panax notoginseng, in healthy volunteers and patients with advanced solid tumors

To evaluate single-dose and multiple-dose pharmacokinetics of panaxatrol disuccinate sodium in healthy volunteers and patients with advanced solid tumors. In the single-dose pharmacokinetic study, 27 healthy volunteers received panaxatrol disuccinate sodium in three doses (70, 100, and 140 mg·m⁻²). In the multiple-dose pharmacokinetic study, Panaxatrol disuccinate sodium was administered to 8 patients at 100 mg·m⁻² daily in a 30-day continuous intravenous injection. Determination of the panaxatrol disuccinate sodium plasma concentration was performed by an LC-MS method. The pharmacokinetic analysis system - Drug and Statistics (DAS) - was applied to assess plasma panaxatrol disuccinate sodium concentration-time data. After a single intravenous dose of 70, 100, or 140 mg·m⁻² was administered to subjects, panaxatrol disuccinate sodium distributed broadly, and the plasma concentration of panaxatrol disuccinate sodium declined rapidly. No significant differences were observed in the main pharmacokinetic parameters among the three dosing groups, including AUC(0-t), MRT(0-t), VRT(0-t), t(1/2Z), CL(z/F), V(z/F), and C₀ (P>0.05). In the multiple-dose pharmacokinetic study, the mean steady-state peak concentration (C(max)), trough concentration (C(min)), average concentration (C(av)), mean steady state AUC (AUC(ss)) and the degree of fluctuation were 13.96±15.48 mg·L⁻¹, 0.18±0.29 mg·L⁻¹, 0.15±0.29 mg·L⁻¹, 3.58±6.94 mg·L⁻¹·h, and 148.00±117.18, respectively. At any given dose of panaxatrol disuccinate sodium, interindividual variability in the pharmacokinetic parameters was obvious. The effect of the dose level on single-dose pharmacokinetics of panaxatrol disuccinate sodium was not significant. No accumulation was observed with exposure to 100 mg·m⁻² panaxatrol disuccinate sodium in the 30-day continuous intravenous injection. All subjects were evaluated for tolerability throughout the study. Thus, the phase II dose of panaxatrol disuccinate sodium may be considered to be 100 mg·m⁻² for a 30-day continuous intravenous injection to treat patients with advanced solid tumors.

Pharmacotherapeutic aspects of treating knee osteoarthritis with glucosamine sulfate

Glucosamine sulfate is a natural constituent of cartilage and is used in the treatment of knee osteoarthritis. The aim of this study is to provide a short but comprehensive pharmacotherapeutic update on treating knee osteoarthritis with glucosamine sulfate. A literature search was conducted of PubMed, Centre for Reviews and Dissemination databases, Cochrane Reviews and EconLit up to January 2010. The literature review indicated that the mechanism of action of glucosamine sulfate is based on hypothesis, but its treatment effects in knee osteoarthritis are symptomatic. With steady-state peak concentrations at the 1,500 mg dosage in the range of 10 µM, it is estimated that only 2% of glucosamine is incorporated in the cartilage. A once-daily dosage of 1,500 mg of glucosamine sulfate is licensed for the treatment of symptomatic osteoarthritis and has been shown to reduce pain, improve function and exhibit similar safety to placebo. Glucosamine sulfate is likely to be a cost-effective treatment of knee osteoarthritis. In conclusion, a once-daily dosage of 1,500 mg of glucosamine sulfate is likely to be a safe, effective and cost-effective treatment of knee osteoarthritis as compared to placebo.

Pharmacokinetic comparison of nomogram-based and individualized vancomycin regimens in neonates

This study compared steady-state concentrations achieved with a dosing strategy using first-dose kinetics to individualize vancomycin regimens with the steady-state concentrations achieved using standardized nomograms. Neonatal intensive care unit patients receiving vancomycin according to published nomograms (phase 1) were compared with patients receiving vancomycin using first-dose pharmacokinetic information to individualize the dosing regimen (phase 2). Retrospective chart review was used to gather demographic and patient-specific pharmacokinetic data. Data collected included gestational and postnatal ages, birth and dosing weights, first-dose peak and trough concentrations, serum creatinine, and information related to infection. Data were analyzed to determine the percentage of therapeutic concentrations at a steady state in each group. Phase 1 included 108 patients given doses according to published nomograms, and phase 2 included 85 patients who received vancomycin with first-dose pharmacokinetics. Steady-state concentrations were collected in 108 patients in phase 1 and 39 patients in phase 2. Both peak and trough concentrations were therapeutic at steady state in 39% in phase 1 versus 63% in phase 2 (p < 0.02). Therapeutic steady-state peak concentrations were achieved in 70% versus 76% while therapeutic steady-state trough concentrations were achieved in 50% versus 82% (p < 0.02) in phase 1 and phase 2, respectively. Compared with the use of nomograms, individualization of vancomycin regimens after the first dose in neonatal patients significantly increased the percentage of patients with target steady-state trough concentrations and with both target peak and trough concentrations. The benefits of individualized dosing were attained without additional venous sampling.