Vancomycin dosing in morbidly obese patients

Objectives and methods: Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal weight population. Results: Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg · kg⁻¹ · d⁻¹ TBW or 81.9 mg · kg⁻¹ · d⁻¹ IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg · kg⁻¹ · d⁻¹ to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2=3.3 h, V=52 l, CL =197 ml · min⁻¹; normal: t1/2=7.2 h, V=46 l, CL=77 ml · min⁻¹, 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW and CL, but only fair correlation between TBW and V. Conclusion: Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when TBW is used as a dosing weight for the obese (approximately 30 mg · kg⁻¹ · d⁻¹). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain above 5 μg · ml⁻¹ in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly obese patients with renal dysfunction require further study. Received: 9 March 1998 / Accepted in revised form: 30 June 1998     

Pharmacokinetics and tissue concentrations of cefazolin in pediatric patients undergoing gastrointestinal surgery

Limited information is available on the pharmacokinetics and tissue penetration of cefazolin in pediatric patients. Nine children (age 0.8-10 years) undergoing gastrointestinal operations were studied. A single dose of cefazolin, 15-26 mg/kg was given i.v. over 2-3 min at the time of induction of anaesthesia. Multiple (5-8) blood samples were collected during the operative procedure and in the recovery room. Tissue samples from the rectus abdominis muscle were obtained at the time of incision, during surgery, and at closure. The concentration of cefazolin was measured by a high performance liquid chromatographic method. Peak serum concentrations of cefazolin ranged from 85.8-269.4 mcg/ml. Serum and tissue concentrations at incision were 50.5-169.9 mcg/ml and 1.8-29.7 mcg/g; at closure the serum and tissue concentrations ranged from 17.3-60.9 mcg/ml and 1.19-29.70 mcg/g, respectively. Total clearance, apparent distribution volume, and elimination half-life of cefazolin were 1.43 +/- 0.54 ml/min/kg, 0.08 +/- 0.03 l/kg, and 1.68 +/- 0.55 h respectively. Tissue concentrations of cefazolin were maintained above its minimum inhibitory concentrations against common susceptible pathogens. Hence, the current dosing regimen of cefazolin is adequate to protect against infection in pediatric patients undergoing gastrointestinal surgery.     

盐酸右美托咪定在全麻肥胖患者体内的药代动力学研究

目的探讨盐酸右美托咪定注射液在中国全麻肥胖患者的药代动力学特征。方法 8例肥胖患者全身麻醉后静脉泵注盐酸右美托咪定1.0μg·kg-1,高效液相色谱-质谱联用法(HPLC-MS/MS)测定血浆中右美托咪定浓度变化。以DAS 2.1.1软件进行数据处理,计算药代动力学参数。结果盐酸右美托咪定的药代动力学参数如下:Cmax为(3.33±1.20)μg·L-1,t1/2α为(2.49±0.56)min,t1/2β为(163.41±116.41)min,V1为(162.96±43.26)L,CLz(4.02±1.18)L·min-1,AUC0-t为(123.27±55.96)μg·min·L-1,MRT0-t为152.06min。肥胖患者的AUC、Cmax、CLz、V1较正常体质量患者均显著增大(P<0.05)。结论在肥胖患者临床麻醉中,给予右美托咪定负荷剂量时,应适当减少药物剂量;维持阶段时,应适当增加药物剂量。     

Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients

Aminoglycoside pharmacokinetics were determined in 30 normal weight patients and 30 morbidly obese patients (greater than 90% overweight). All had normal renal function and a gram-negative infection (documented by cultures, fever and elevated white blood cell counts) which was treated only with aminoglycoside antibiotics. The normal weight and morbidly obese patients were matched with respect to the following criterion: age, sex, ideal body weight (IBW), serum creatinine, site of infection, and type of aminoglycoside antibiotic (gentamicin, tobramycin, or amikacin). The results were similar for all 3 drugs. Average half-life was 2 h for both the morbidly obese and normal weight patients. The mean volumes of distribution and clearances were significantly larger in the morbidly obese (23.3 l and 135.8 ml/min for gentamicin, 29.9 l and 162.4 ml/min for tobramycin, and 26.8 l and 157.3 ml/min for amikacin) than in normal weight patients (17.0 l and 95.9 ml/min for gentamicin, 18.3 l and 101.3 ml/min for tobramycin, and 18.6 l and 99.2 ml/min for amikacin). As a result of altered aminoglycoside pharmacokinetics, morbidly obese patients required significantly larger mean doses (540 mg/d for gentamicin, 690 mg/d for tobramycin and 1970 mg/d for amikacin) when compared to the normal weight patients (380 mg/d, 420 mg/d and 1420 mg/d, respectively; p less than 0.005) in order to achieve comparable serum concentrations.     

Pharmacokinetics and protein binding of eprosartan in hemodialysis-dependent patients with end-stage renal disease.

STUDY OBJECTIVES: To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values. DESIGN: Open-label, parallel-group, single-dose study. SETTING: Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. PATIENTS: Ten healthy volunteers and nine hemodialysis patients. INTERVENTION: A single oral dose of eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis. MEASUREMENTS AND MAIN RESULTS: Concentrations of eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC(0-t) was increased approximately 60% (95% CI-22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI -40, 71). Mean percent fraction unbound (%f(u)) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC(0-t) and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI -1, 199) greater, respectively, in patients. After hemodialysis, the mean %f(u) decreased from 3.19-2.01%. Mean recovery of eprosartan in dialysate was 6.8 mg (range 0-23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance. CONCLUSIONS: Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of eprosartan after hemodialysis are unnecessary.     

Protein binding of cefazolin is saturable in vivo both between and within patients

AIMS: The aims of the study were a) to determine if there is evidence of saturable protein binding of cefazolin in plasma across the range of concentrations achieved clinically (between patient variability) and b) to investigate whether saturable protein binding is also evident from trough and peak concentrations in the same patient (within patient variability). METHODS: Unbound and total plasma concentrations were measured in patients who were treated with cefazolin intravenously by continuous infusion or intermittent injection. In study (i) single random samples were taken from one series of patients. In study (ii) paired samples (troughs and peaks) were taken from a second series of patients. RESULTS: Thirty-one patients were included in study (i). Linear regression analysis of the percentage unbound vs. unbound plasma concentrations revealed a slope significantly different from zero, suggesting saturable protein binding. Mean values for percentage unbound ranged from 9% at low concentrations (8.5 mg l(-1)) to 51% at high concentrations (140 mg l(-1)). Twelve patients were investigated in study (ii). Values for protein binding ranged from 85% at low concentrations (2.7 mg l(-1)) to 52% at high concentrations (200.3 mg l(-1)). The percentage unbound was significantly higher (P < 0.0001) at high (peak) concentrations than at lower (trough) concentrations, confirming saturable protein binding. CONCLUSIONS: The protein binding of cefazolin is saturable in vivo in humans, both between and within patients.     

Studies on protein binding of antibiotics. II. Effect of apalcillin on protein binding and pharmacokinetics of cefoperazone and cefazolin

The drug-protein interactions between cefoperazone (CPZ) and apalcillin (APPC), and between cefazolin (CEZ) and APPC were investigated in in vitro and in vivo experiments. Through the binding rates of CPZ or CEZ to rabbit serum and human serum albumin subsided remarkably with increased drug concentrations, APPC was not greatly affected, even at high concentrations. It appeared that APPC had a higher binding capacity to protein than CPZ or CEZ. From the results of competitive study, it became clear that APPC partially shared the binding sites on protein with CPZ or CEZ. The CPZ or CEZ serum levels in rabbits administered together with APPC were not different from those for the single administration, but APPC levels for the simultaneous administration were slightly lower.     

Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance

Aims N -Desmethylclozapine and clozapine N -oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.
Methods From 15  psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2  h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.
Results The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N -desmethylclozapine 9.7%, and clozapine N -oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N -desmethylclozapine and clozapine N -oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N -desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.
Conclusions Clozapine, N -desmethylclozapine and clozapine N -oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N -demethylation and N -oxidation must make major contributions to the total fate of clozapine in patients.     

Surgically affected sulfisoxazole pharmacokinetics in the morbidly obese

Intestinal bypass surgery in 4 morbidly obese females (110-150 kg) had no permanent effect on the rate or amount of sulfisoxazole absorption. The loss of weight up to 44 per cent within an individual over a year's time had no significant effect on the apparent volumes of distribution or other pharmacokinetic parameters of sulfisoxazole and its N⁴- acetylsulfisoxazole metabolite. Dosing of this drug on a mgkg^{? 1} basis is contraindicated. Renal clearances of sulfisoxazole were reasonably constant within a study but those of the N⁴-acetylsulfisoxazole decreased with time. Integrated pharmacokinetic models were applied to plasma and urine data to estimate the metabolic clearance of sulfisoxazole and the apparent volume of distribution of the N⁴-acetylsulfisoxazole. Sulfisoxazole solution is absorbed readily by primarily a zero order process after a short lag period, indicative of rate-determining gastric emptying. The classical Bratton-Marshall assays were compared with an HPLC assay of both drug and metabolite. There was greater confidence in plasma levels of the metabolite from the HPLC method.     

Pharmacokinetics and protein binding of MPT0B292

MPT0B292 was identified through screening of compounds able selectively to acetylate α‐tubulins in cells and it exhibited potent anti‐tumor, anti‐angiogenesis and anti‐metastatic effects in vitro and in vivo . Because of its poor water solubility, MPT0B292 is difficult to formulate with conventional approaches and hence difficulties are experienced in research practices. MPT0B292 was mixed with albumin in an aqueous solvent to form drug albumin nanoparticles with a size range around 333 nm. Unbound fractions of these nanoparticles were investigated in different or the same albumin concentration solutions. Unlike most drugs, the binding of MPT0B292 in human serum albumin increased with increasing drug concentrations. An analytical method was also developed and validated to determine MPT0B292 in rat plasma. This analytical method was applied successfully to the intravenous pharmacokinetic study of MPT0B292 in rats. A single dose study was regularly done to characterize the pharmacokinetic properties of the drug. Additionally, a novel i.v. infusion study was carried out to verify the extraction ratio of MPT0B292. The pharmacokinetic analysis revealed that MPT0B292 was a high extraction ratio drug with high systemic clearance, a high volume of distribution and a short half‐life in rats. Copyright © 2017 John Wiley & Sons, Ltd.     

Cefamandole distribution in serum, adipose tissue, and wound drainage in morbidly obese patients

Distribution and elimination of cefamandole 2 g iv were studied in 11 morbidly obese patients during a gastric bypass operation and again on the first postoperative day. Serum, subcutaneous adipose tissue, wound drainage, and urine were analyzed by high performance liquid chromatography for cefamandole and pharmacokinetic parameters from the intraoperative period were compared to those obtained postoperatively. Total body clearance was significantly greater (p less than 0.001) postoperatively (297 ml/min) than intraoperatively (254 ml/min). Volume changes were unpredictable but the elimination rate constant tended to increase postoperatively. Renal clearance and percentage of urinary recovery were significantly increased (p less than 0.01) postoperatively. The patients had a mean (+/- SD) volume of the central compartment of 10.3 (+/- 2.3) L, volume at steady state of 18.3 (+/- 3.9) L, and elimination rate constant of 1.67 (+/- 0.63) h-1. Tissue concentrations of cefamandole were highest during the first hour after drug administration and were less than 1 microgram/g after 3.5 hours. Mean wound drainage concentrations ranged between 10 and 12 micrograms/ml during a dosing interval and dropped to 7 micrograms/ml 12 hours after the last dose. Intraoperative dosing of cefamandole is required to maintain subcutaneous adipose tissue concentrations greater than 1 microgram/g during procedures longer than three hours in morbidly obese patients. A postoperative dose of cefamandole 2 g iv q6h will provide sustained and therapeutic concentrations in the wound drainage of morbidly obese patients.     

Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals

Summary We determined plasma methocarbamol concentrations over 24 h following a 1.5 g methocarbamol dose (off-dialysis day) to 8 chronic haemodialysis patients and compared these results to those from 17 healthy male volunteers.The harmonic mean elimination half-life was similar between the two groups, 1.24 and 1.14 h, respectively. t_max and the weight-adjusted C_max were 1.1 h and 27.0 mg · m^–1 for haemodialysis patients and 1.1 and 23.1 mg · l^–1 for normals. Relative systemic availability was assessed by comparing weight-normalized AUC × k₁₀ products.These results indicate no significant differences with respect to methocarbamol absorption, with the relative systemic availability in patients being 113%.These data suggest that absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance haemodialysis.     

Pharmacokinetics and protein binding interactions of dapsone and pyrimethamine.

1 Seven normal volunteers received oral doses of 100 mg dapsone (DDS), 25 mg pyrimethamine (PYR) singly or in combination in random order. 2 Plasma and salivary DDS and plasma monoacetyldapone (MADDS) and PYR were estimated simultaneously by a hitherto unpublished quantitative absorption thin layer chromatographic method. This assay was shown to be satisfactory for pharmacokinetic studies. 3 The half-life of DDS was unaltered by PYR but the apparent volume of distribution was significantly increased from a mean of 1.53 1 kg-1 to 1.93 1 kg-1 and the peak DDS plasma levels measured fell by 17%. 4 The pharmacokinetic parameters of PYR were unchanged by DDS. 5 The half-life of MADDS was unchanged by PYR and was not affected by the acetylator status of the subject. 6 Salivary DDS excretion reflects the free plasma DDS concentration. Administration of PYR with DDS significantly alters the mean saliva/plasma DDS ratio from 0.265 to 0.358 suggesting an increase in free DDS with PYR therapy. 7 In vitro studies of plasma protein DDS binding indicate that DDS binds to a single class of binding sites on human plasma protein and PYR competitively displaces DDS from these sites. 8 The usefulness of salivary drug measurements in detecting increases of free drug in plasma in man is demonstrated.     

The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects

Daptomycin pharmacokinetics were studied in adult volunteers who were moderately obese (body mass index [BMI] = 25-39.9 kg/m2) or morbidly obese (BMI > or =40 kg/m2) and a matched (gender, age, renal function) nonobese (BMI between 18.5 and 24.9 kg/m2) control group. All subjects received a dose of 4 mg/kg total body weight (TBW) by intravenous infusion (30 minutes). Daptomycin plasma half-life, the fraction of the dose excreted unchanged in urine, and daptomycin absolute renal clearance (mL/h) were unchanged as a function of obesity. The absolute volume of distribution (Vz and Vss) and plasma clearance (CL) for daptomycin were higher in obese subjects as compared to nonobese matched controls. The rate of change of Vz and CL with increasing BMI was greater when these pharmacokinetic parameters were expressed in absolute terms compared to when they were normalized for TBW or ideal body weight. This suggests that increases in body mass associated with obesity are proportionality higher than the corresponding increases in Vd and CL. Exposure to daptomycin in obese subjects (Cmax, AUC) was increased 25% and 30%, respectively, compared to nonobese matched controls, well within the range that was previously determined to be safe and well tolerated. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.     

Pharmacokinetics of quinidine related to plasma protein binding in man

Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant () varied from 0.071 to 0.146 h^–1 (mean 0.113), and apparent volume of distribution (V) varied from 1.39–3.20 l · kg^–1 (mean 2.27). Total body clearance was 2.32–6.49 ml min^–1 · kg^–1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both V (r=0.885, p<0.01) and total body clearance (r=0.668, p<0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.