A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A retrospective study was conducted to assess our 10‐year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C_min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C_min was set between 2 and 7 mg/L (underexposure, C_min < 2 mg/L; overexposure, C_min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C_min. One thousand and forty‐nine patients had 2484 linezolid C_min assessed during treatment with conventional doses. Median (IQR) linezolid C_min was 5.08 mg/L (2.78–8.52 mg/L). Linezolid C_min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL_C‐G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124–1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL_C‐G estimates >100 mL/min. (OR 3.046; 95% CI 2.234–4.152, p < 0.001). Linezolid C_min was not correlated linearly with CrCL_C‐G (R² = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C_min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.     

Clinical pharmacology of tocilizumab for the treatment of polyarticular-course juvenile idiopathic arthritis

Introduction: The efficacy and safety of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor (IL-6R) monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) were demonstrated in clinical trials.

Area covered: A literature search was undertaken in the public domain from 1995 to 2016. Data included in the regulatory submission leading to approval of TCZ for the treatment of pJIA in the European Union, United States, and Japan were also presented. TCZ 10 mg/kg in patients weighing <30 kg provided pharmacokinetic exposure comparable to that of TCZ 8 mg/kg for patients ≥30 kg. Pharmacodynamic (C-reactive protein, erythrocyte sedimentation rate, IL-6, and soluble IL-6R) and efficacy outcomes were comparable between TCZ 10 mg/kg in patients <30 kg and TCZ 8 mg/kg in patients ≥30 kg. Proportions of patients achieving JIA ACR 30/50/70/90 responses at week 16 increased with higher exposure (mean±SD C_min from quartile 1 to quartile 4: 0.02 ± 0.047, 0.98 ± 0.707, 5.00 ± 1.73, and 16.54 ± 7.74 µg/mL; n = 42). The adverse event rate did not increase with increased exposure. Data support weight–based dosing regimens.

Expert commentary: Biologics have improved outcomes for patients with pJIA with inadequate response to conventional therapy. TCZ will likely become an increasingly important treatment option for the management of pJIA.     

Steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected Chinese patients

Background: The pharmacokinetic (PK) profile of tenofovir disoproxil fumarate in Chinese adults infected with HIV is unknown.

Methods: A pilot, prospective, open-label study was performed to investigate the steady-state PK profile of tenofovir disoproxil fumarate in 15 Chinese HIV-infected patients among whom eight patients were treated with 300 mg tenofovir disoproxil fumarate, 300 mg lamivudine and 400/100 mg lopinavir/ritonavir, and seven with 300 mg tenofovir disoproxil fumarate, 300 mg lamivudine and 400 mg nevirapine. The plasma concentrations of tenofovir over the 24-h dosing interval were determined by HPLC. The PK parameters were calculated using the non-compartmental model in WinNonlin software.

Results: The PK parameters of tenofovir in the 15 patients were determined as follows (mean ± SD): AUC_{(0-24 h)}, 4074.7 ± 1551.9 ng?h/mL; C_max,ss, 447.1 ± 217.4 ng/mL; C_trough,ss, 98.7 ± 36.7 ng/mL; t_max,ss, 1.3 ± 0.4 h; plasma t_1/2, 21.8 ± 7.6 h; and CL_ss/F, 45.8 ± 13.0 L/h.

Conclusion: Tenofovir demonstrated slower elimination rate and increased plasma concentration in Chinese patients compared to previously published data from Caucasian or African subjects, which may be associated with the higher incidences of renal and bone resorption dysfunction observed in our patient population. Clinicians should be cautious of the differing PK characteristics of tenofovir among people of different races.     

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients

Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9–22). Blood samples were investigated for pharmacokinetic parameters before and 7–14 days after the conversion. Fifteen patients were included and provided AUC_0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p = 0.41). Mean trough blood concentration (C_min) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p = 0.01). Correlation coefficient (r) between C_min and AUC_0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of C_min > 30% had a significant lower AUC_0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of C_min > 30% after conversion to TAC-OD will require additional dose adjustment.     

Lispro administered by the QS-M Needle-Free Jet Injector generates an earlier insulin exposure

ABSTRACT

Objective: The aim of this study is to evaluate the pharmacokinetic and pharmacodynamic (PK-PD) profiles of lispro administered by the QS-M needle-free jet injector in Chinese subjects.

Research design and methods: A randomized, double-blind, double-dummy, cross-over study was performed. Eighteen healthy volunteers were recruited. Lispro (0.2 units/kg) was administered by the QS-M needle-free jet injector or by conventional pen. Seven-hour euglycemic clamp tests were performed.

Results: A larger area under the curve (AUCs) of insulin concentration and glucose infusion rate (GIR) during the first 20 minutes after lispro injection by the jet injector compared to the insulin pen was observed (24.91 ± 15.25 vs. 12.52 ± 7.60 mg. kg^?1, P < 0.001 for AUC_{GIR,0–20 min}; 0.36 ± 0.24 vs. 0.10 ± 0.04 U min L^?1, P < 0.001 for AUC_{INS, 0–20 min}). Needle-free injection showed a shorter time to reach maximum insulin concentration (37.78 ± 11.14 vs. 80.56 ± 37.18 min, P < 0.001) and GIR (73.24 ± 29.89 vs. 116.18 ± 51.89 min, P = 0.006). There were no differences in total insulin exposure and hypoglycemic effects between the two devices.

Conclusion: Lispro administered by QS-M needle-free injector results in earlier and higher insulin exposure than conventional pen, and a greater early glucose-lowering effect with similar overall potency.     

Evaluation of super-boosted lopinavir/ritonavir in combination with rifampicin in HIV-1-infected patients with tuberculosis

Rifampicin induces the metabolism of many drugs. To overcome the reduction in serum concentrations of lopinavir/ritonavir (LPV/r) when used in combination with rifampicin, 800/200 mg or 400/400 mg doses are used. This study evaluated super-boosted LPV/r (400/400 mg) in HIV/TB co-infected patients for adequate concentrations as well as short-term safety, tolerability and clinical response to therapy. This was an open-label, non-randomised pharmacokinetic (PK) study in HIV/TB patients. The primary objective was to determine the PK profile of super-boosted LPV/r when given with a rifampicin-based TB regimen. Secondary objectives were short-term safety, tolerability and clinical response. Primary endpoints were a lopinavir trough concentration (C_min) >1.0 µg/mL and a rifampicin maximum concentration (C_max) of 8–24 µg/mL. Secondary PK endpoints were a rifampicin area under the concentration–time curve from 0–24 h (AUC_0–24) of 44–70 µg·h/mL, a lopinavir C_max of 6–14 µg/mL and a lopinavir AUC_0–12 of 56–130 µg·h/mL. Eleven patients (10 male, age 25–43 years) were enrolled. Two patients were discontinued due to non-compliance. A lopinavir C_min of >1.0 µg/mL was achieved in a least one of the PK samplings in all nine subjects who completed treatment. All patients met lopinavir C_max and AUC_0–12 targets. Five patients achieved the primary endpoint of rifampicin C_max (≥8 µg/mL) in at least one of the PK samplings, and five achieved the minimum rifampicin AUC_0–24 (≥44 µg·h/mL). One grade 3 adverse event was reported. Super-boosted LPV/r was safe and effective in HIV/TB patients. [ClinicalTrials.gov ID NCT01700790.]     

Impact of total body weight on acute kidney injury in patients with gram-negative bacteremia

Background: The impact of total body weight (TBW) on the development of acute kidney injury (AKI) associated with gram-negative bacteremia has not been previously evaluated.

Methods: The cohort included 323 patients >/ = 18 years old with gram-negative bacteremia (1/1/2008–8/31/2011) who received >/ = 48 hours of antibiotics. We compared the incidence of AKI in patients with a TBW </ = 80kg vs. >80kg with a multivariable stepwise logistic regression adjusting for age >/ = 70 years, baseline serum creatinine of > 2.0 mg/dl, and receipt of a vasopressor. AKI was defined as an increase of 0.5 mg/dL or a > 50% increase from baseline for at least two consecutive days.

Results: The cohort was 62% TBW </ = 80kg and 38% TBW >80kg. TBW >80kg patients had higher risk of AKI (24% vs. 9%, p < 0.001), which was significant in the multivariable analysis (OR 3.41, 95% CI 1.73–6.73). A baseline serum creatinine of > 2.0 mg/dl and vasopressor use were also independently associated with AKI.

Conclusions: TBW >80kg was associated with the development of AKI. However, the mechanism for this association is not clear.     

Impact of increased venous pressure on kidney function and mortality in cardiovascular patients with preserved ejection fraction

Abstract

Background: Right but not left ventricular hemodynamic parameters have been found to be independently associated with adverse renal outcomes in patients with acute decompensated heart failure (HF).

Aim: To investigate the hemodynamic profile of patients without acute decompensated heart failure and left ventricular ejection fraction >50% referred for elective left and right heart catheterization and to correlate left and right filling pressures, stroke volume and arterial blood pressure to renal function parameters. Subsequently, we tested the hypothesis that right ventricle and left ventricle hemodynamic parameters can predict all-cause mortality in our non-HF subjects.

Methods: Between October 2009 and November 2010, 151 consecutive patients referred for elective left and right heart catheterization were studied and consequently followed up for a mean period of 8?years in order to identify all-cause mortality. Patient’s initial cohort was subdivided in two groups according to right atrial pressure. The RAPR_LOW group (Right Atrium Pressure ≤ 9?mmHg) and the RAPR_HIGH group (Right Atrium Pressure > 9mmHg)

Results: No correlation between blood pressure, pulmonary capillary wedges pressure, cardiac index, stroke volume and stroke volume index (SVI), and parameters of kidney function was observed. However, a weak, although, significant correlation between right atrial pressure (RAP) and modification of diet in renal disease (MDRD) (r = –0.202; p?=?.014) could be detected. RAPR_LOW patients had a statistically significant lower MDRD value of 16.6?mL/min/1.73 m² than RAPR_HIGH patients. Increased RAP (HR = 2.03; 95% [CI]: 1.05 to 3.9; p?=?.025) and age (HR = 1.08, 95% [CI] 1.04–1.12, p?<?.001) independently predicted all-cause mortality during follow up.

Conclusions: Our study demonstrates that right ventricular preload affects renal function in patients with preserved systolic function and that neither aortic systolic pressure nor left ventricle pressure indices were related to estimated glomerular filtration rate. Furthermore, we demonstrate for the first time that an increased RAP is able to predict a worse prognosis in patients with preserved ejection fraction independently of well-established risk factors, such as blood pressure and SVI.     

Abaloparatide in patients with mild or moderate renal impairment: results from the ACTIVE phase 3 trial

Abstract

Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment.

Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80?µg, placebo, or open-label teriparatide 20?µg daily. Patients with serum creatinine >2.0?mg/dL or 1.5–2.0?mg/dL with an estimated glomerular filtration rate (eGFR) <37?mL/min, calculated by Cockcroft-Gault formula, were excluded.

Results: At baseline, 660 patients had eGFR ≥90?mL/min, 1276 had 60 to ?90?mL/min, and 527 had <60?mL/min. Older age and lower T-scores were associated with greater renal impairment. Among renal-function subgroups, there were no meaningful changes in bone mineral density, fracture risk reduction, or overall incidence of treatment-emergent adverse events in the active-treatment arms. Anemia, nausea, hypercalcemia, and upper-respiratory-tract infection tended to be more frequent with increasing renal impairment. Hypercalcemia measured by albumin-adjusted serum calcium occurred significantly less frequently with abaloparatide than teriparatide in patients with eGFR <60?mL/min (3.6% versus 10.9%; p?=?.008) and in the overall ACTIVE safety population (3.4% versus 6.4%; p?=?.006). Computed tomography scans in 376 patients revealed no evidence of increased renal calcification.

Conclusion: Increased exposure to abaloparatide and teriparatide in patients with renal impairment led to no meaningful differences in efficacy or safety. These results support the use of abaloparatide without dosage adjustment in patients with renal impairment, provided those with severe renal impairments are monitored for adverse events.     

Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection

Purpose

Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections.

Method

This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥60 kg with a normal renal function or with a creatinine clearance (CL_CR) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CL_CR of 10–20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed <60 kg were administered 50,000 IU/kg/day in three divided doses at 8-h intervals. Both single-dose and steady-state pharmacokinetics of colistin were determined and correlated with clinical outcomes.

Results

A wide inter-individual variation was observed in pharmacokinetic parameters. The median (range) of the maximum plasma drug concentration/minimum inhibitory concentration (C_max/MIC) ratio for Acinetobacter spp. was 13.4 (1.3–40.3) following the administration of a single dose of colistimethate sodium and 26.3 (0.9–64.9) at steady-state. For Pseudomonas spp., these values were 3.18 (1.6–23.1) following the single dose and 3.82 (2.3–10.9) at steady-state. For those patients whose cultures grew Acinetobacter spp., an optimum value of the C_max/MIC ratio of >8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a C_max/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality.

Conclusion

The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the C_max/MIC ratio to an optimal level—at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight.

     

Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance

ObjectiveTo determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection.MethodsARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated.ResultsMean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V_ss) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V_ss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate.ConclusionsIn patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam.ClinicalTrials.gov identifierNCT02387372     

Impaired renal function and atherosclerosis in a Pakistani cohort

ABSTRACT

Objective: To investigate the relationship of creatinine and calculated glomerular filtration rate (GFR) with coronary arterial disease (CAD) in Pakistani patients.

Subjects: Four hundred individuals with chest pain; 200 with angiographic disease matched with 200 without occlusive disease.

Design: A prospective case-control study.

Setting: A tertiary referral cardiology unit in Pakistan.

Results: Impaired renal function as estimated by calculated GFR was common in this population. Creatinine and glomerular filtration rate, as calculated by the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae, were associated with CAD and atherosclerotic burden in Pakistani patients. Calculation of creatinine clearance, correcting for age, sex and body mass index, showed that clearance was 81 (17–257)?mL/min/1.73?m² in patients with CAD compared with 88 (23–167)?mL/min/1.73?m² in controls with a significant number of patients (18.5 vs. 6.5%; RR = 2.85; p < 0.001) showing significant renal impairment (< 60?mL/min/1.73?m²) by CG and more by the MDRD equation (26 vs. 9%; RR = 2.88; p < 0.001). The unadjusted odds ratios for CAD for a GFR < 60?mL/min/1.73?m² were 3.66 (1.87–7.16) and 3.29 (1.81–6.01), respectively and, after adjustment for diabetes, smoking, insulin resistance, inflammation and apolipoprotein A1, 1.04 (1.02–1.09) and 1.04 (1.02–1.09), respectively.

Conclusions: Impaired renal function is common in Pakistani patients with coronary arterial disease and is strongly associated with a risk of atherosclerosis independent of insulin resistance.     

利奈唑胺血药浓度监测研究进展

目的介绍利奈唑胺血药浓度监测的研究进展。方法在PubMed、中国知网、万方医学网及FMJS等数据库组合检索2002年2月—2021年4月期间的文献,筛选出利奈唑胺血药浓度监测下有关疗效和安全性的相关文献,综合分析血药浓度监测下利奈唑胺疗效和安全性的谷浓度范围。结果共检索到相关文献156篇,其中有效文献30篇。利奈唑胺在不同感染患者中的有效血浆谷浓度(Cmin)是不同的,多数研究认为Cmin>2.0 mg·L^-1时有效,即谷浓度范围的低限通常为2.0 mg·L^-1;就安全性而言,目前研究对利奈唑胺血浆谷浓度范围高限的确定不一致,最低为6.3 mg·L^-1,最高可达22.1 mg·L^-1。结论临床在使用利奈唑胺时,应该监测血药浓度,以达到既保证疗效又能降低不良事件发生的目的。     

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

SUMMARY

Objective: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40?mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C.

Research design and methods: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA_1C < 9%), low density lipoprotein-cholesterol (LDL-C) > 100?mg/dL (2.6?mmol/L), HDL-C < 40?mg/dL (< 1?mmol/L), and fasting triglyceride level > 150 (> 1.7?mmol/L) and < 700?mg/dL (< 7.9?mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States.

Main outcome measures: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval.

Results: Both simvastatin 80 and 40?mg significantly increased total HDL-C from baseline (mean increases of 8% ± 1 [SE] and 5% ± 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (?p < 0.001), triglycerides (?p < 0.001), apolipoprotein B (?p < 0.001), and hs-CRP (?p ≤ 0.012). Compared with simvastatin 40?mg, the 80?mg dose provided additional efficacy. Simvastatin 80?mg also significantly (?p < 0.001) increased HDL₂ from baseline (14% ± 3[SE]) and placebo phases (10 ± 3). An exploratory analysis showed 87% (simvastatin 80?mg) and 82% (simvastatin 40?mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo.

Conclusions: Both simvastatin 80 and 40?mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

Dose Regimen Adjustment for Milrinone in Congestive Heart Failure Patients with Moderate and Severe Renal Failure

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 μg kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0·45 or 0·35 μg kg^?1 min^?1 for the moderate (chromium-EDTA clearance of 31–75 mL min^?1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10–30 mL min^?1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (± s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100–300 ng mL^?1) for both groups, with values of 239 ± 71 ng mL^?1 and 269 ± 32 ng mL^?1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL^?1, that were not associated with any serious adverse events. As predicted for this highly renally cleared drug, there were differences (P < 0·001) in the total plasma clearance (CL_P), renal clearance (CL_r), and plasma terminal half-life (t1/2) of drug, with values in the severe group being 44% lower, 75% lower, and about 134% longer respectively, when compared with the moderate group. High (correlation coefficient > 0·8) and significant correlations (P < 0·001) were observed between CL_P and CL_r and the degree of renal impairment (chromium-EDTA clearance). The apparent volume of distribution was approximately 40% higher (P < 0·01) in the severe group compared with that for the moderate group (moderates were 0·443 ± 0·155 L kg^?1). This volume difference suggests a decrease in the plasma protein-binding of milrinone because of the renal disease. The fraction of drug excreted in the urine was 0·705 ± 0·100 for the moderate group and 0·320 ± 0·089 for the severe group (P < 0·001). These results may suggest an increase in non-renal clearance of the compound, representing a partial compensation mechanism for the reduced renal function. In conclusion, this study has confirmed that the current dose reductions recommended for the use of intravenous milrinone in CHF patients with impaired renal function will yield plasma concentrations of the drug within the therapeutic range.     

Mefloquine Effect on Disposition of Halofantrine in the Isolated Perfused Rat Liver

Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine. Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean ± s.d.) were: volume of distribution (Vd), 7.53 ± 1.45 mL (g liver)^?1; clearance (CL), 0.11 ± 0.07 mL min^?1 (g liver)^?1; initial distribution half-life (initial t1/2), 14.62 ± 2.38 min; terminal half-life (terminal t1/2), 138.7 ± 178.8 min; AUC 606 ± 194 mg mL^?1 min^?1 (g liver)^?1; elimination rate constant (K_e), 0.0135 ± 0.012 min^?1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, K_e, initial and terminal t1/2 (P > 0.05). A single dose, short term (4?6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefioquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 005) and biliary clearance (P < 005) of halofantrine in mefioquine-pretreated livers. These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.     

Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication

Background: Dexmedetomidine is a widely used sedative in clinic, which is mainly metabolized by cytochrome P450 2A6 (CYP2A6). Dexmedetomidine was rarely reported for off-label usage of premedication, but lacking relevant pharmacokinetic investigations. Therefore, our study determined the dexmedetomidine pharmacokinetics of CYP2A6*4 allele in Chinese patients pretreated with dexmedetomidine whose mutation frequency of CYP2A6*4 are high, in order to provide clinical references.

Methods: Thirty-one elective surgery patients received premedication with 0.5 μg/kg dexmedetomidine via intravenous pump. Their plasma concentrations at multiple time-points and polymorphism of CYP2A6*4 were determined and statistically analyzed.

Results: 9 patients were *1/*4 or *4/*4, and 22 patients were *1/*1. The main pharmacokinetic parameters were area under curve (AUC) 1396.19 ± 332.47h· ng· l^?1, peak blood concentration (C_max) 495.50 ± 104.90ng· l^?1, distribution volume (V) 0.68 ± 0.20 L/kg, clearance (CL) 0.38 ± 0.11 L/h/kg, distribution half-life (t_1/2α) 0.05 ± 0.01h, elimination half-life (t_1/2β) 2.53 ± 0.04h. No significant pharmacokinetic differences were found among CYP2A6*1/*1, *1/*4, and *4/*4 patients.

Conclusions: In Chinese patients pretreated with dexmedetomidine, T_1/2β was consistent with that published, but T_1/2α, V and Cl were lower. It was unnecessary to consider the mutation when developing the precision regimen of dexmedetomidine.     

Population pharmacokinetics–pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5–15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory E_max function of C_min on the seizure mean, where E_max exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in E_max. The dependence of seizure frequencies on C_min was explored by simulation. The responder rate increased with increasing C_min. As C_min decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5–15 ng/mL to ensure treatment efficacy.     

Time course of arsenic species in red blood cells of acute promyelocytic leukemia (APL) patients treated with single agent arsenic trioxide

Background:Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). To elucidate metabolism and toxicity of arsenic, we analyzed time course of arsenic species in red blood cells (RBCs) of APL patients.

Methods:Nine APL patients received ATO (0.16 mg/kg/day) through 18-h infusion. Blood was collected before daily administration (days 2 to 9), and at different time points on day 8. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were detected by HPLC-ICP-MS.

Results:Arsenic species reached C_max at 18 h on day 8. Arsenicals gradually accumulated during days 2 to 9, whereas their percentages remained almost constant. The general trend in red blood cells (RBCs) was iAs > MMA > DMA. MMA was consistently the predominant methylated arsenic metabolite in RBCs. iAs, MMA, and tAs (tAs = iAs + DMA + MMA) concentrations (P < 0.0001), MMA/DMA ratios (P = 0.0016) and iAs% (P = 0.0013) were higher in RBCs than in plasma.

Conclusions:Time course of arsenic species reveal kinetic characteristic of ATO metabolites in RBCs. Arsenic species accumulated with administration frequency. Arsenic species in RBCs were remarkably different from those in plasma. Time course of arsenic species in RBCs is important in ATO clinical application.