Therapeutic drug monitoring of tobramycin: once-daily versus twice-daily dosage schedules

Objective: To evaluate the effect of dosage regimen (once-daily vs. twice-daily) of tobramicyn on steady-state serum concentrations and toxicity. Materials and methods: Patients undergoing treatment with iv tobramycin (4 mg/kg/day) were randomised to two groups. Group OD ( n=22) received a once-daily dose of tobramycin and group TD (n=21) received the same dose divided into two doses daily. Tobramycin serum concentrations (peak and trough) were measured by enzyme multiplied immunoassay. The renal and auditorory functions of the patients were monitored before, during and immediately after treatment. Results: The two groups were comparable with respect to sex, age, body weight and renal function. No statistically significant differences were found in mean daily dose, duration of treatment, or cumulative dose. Trough concentrations were < 2 μg/ml in the two groups (100%). Peak concentrations were > 6 μg/ml in 100% of the OD group and in 67% of the TD group ( P< 0·01). Mean peak concentrations were markedly different: 11·00±2·89 μg/ml in OD vs. 6·53±1·45 μg/ml in TD ( P< 0·01). The pharmacokinetics parameters were: K_e, (0·15±0·03/h in OD vs. 0·24±0·06/h in TD), t_1/2, (4·95±1·41 h in OD vs. 3·07±0·71 h in TD), V_d (0·35±0·11 l/kg in OD vs. 0·33±0·09 l/kg in TD), Cl (0·86±0·29 ml/min/kg in OD vs. 1·28±0·33 ml/min/kg in TD). Increased serum creatinine was observed in 73% of patients in OD versus 57% of patients in TD, without evidence of nephrotoxicity. In TD group, three patients developed decreased auditory function, of which one presented with an auditory loss of –30 dB, whereas in the OD group only one patient presented decreased auditory function. Conclusion: This small study suggests that a once-daily dosing regimen of tobramycin is at least as effective as and is no more and possibly less toxic than the twice-daily regimen. Using a single-dose therapy, peak concentration determination is not necessary, only trough samples should be monitored to ensure levels below 2 μg/ml.     

Appropriateness of a 4 mg/kg gentamicin or tobramycin loading dose in post-operative septic shock patients

Objective: To determine the frequency with which early adequate peak serum concentrations (6–12 mg/litre) can be achieved following a 4 mg/kg loading dose of gentamicin or tobramycin in post-operative septic shock patients. Method: Eleven post-operative septic shock patients were grouped into (i) a control group ( n=7) who received the conventionl gentamicin or tobramycin dosing regimen of 2 mg/kg loading dose followed by a maintenance dose of approximately 1·5 mg/kg (peak and trough levels were measured after the third dose), and (ii) a study group ( n=4) who received a tobramycin or gentamicin 4 mg/kg loading dose, followed by 30 min, 3 h and 16 h serum drug level measurements. Pharmacokinetic parameters were calculated using a one-compartmental model. Differences in both groups were determined using Student's t-test. Results: Pharmacokinetic parameters in both groups showed no statistically significant difference. The dose from which peak levels were drawn was significantly higher in the study group (4 mg/kg vs. 1·66 mg/kg; P=0·001), which also resulted in higher but adequate peak serum concentrations (8·9±2·2 vs. 4·8±1·8 mg/litre). In the study group, linear regression analysis showed significant relationships between dose and peak concentrations and volume of distribution and peak concentrations ( r=0·96, P=0·01 and r=?0·96, P=0·01, respectively). Conclusion: One hundred per cent of the post-operative septic shock patients achieved target peak serum concentrations (mean 8·9±2·2 mg/litre) following a 4 mg/kg tobramycin or gentamicin loading dose. An expanded V_d (0·46±0·13 litres/kg) was also observed.     

Once daily dosing of netilmicin in neonatal and pediatric intensive care

Objective To examine a once daily dosing regimen of netilmicin in critically ill neonates and children.Design and setting Open, prospective study on 81 antibiotic courses in 77 critically ill neonates and children, hospitalized in a multidisciplinary pediatric/neonatal intensive care unit. For combined empiric therapy (aminoglycoside and beta-lactam), netilmicin was given intravenously over 5 min once every 24 h. The dose ranged from 3.5–6 mg/kg, mainly depending upon gestational and postnatal age. Peak levels were determined by immunoassay 30 min after the second dose and trough levels 1 h before the third and fifth dose or after adaptation of dosing.Results All peak levels (n=28) were clearly above 12 mol/l (mean 22, range 13–41 mol/l). Eighty-nine trough levels were within desired limits (<4 mol/l) and 11 (11%) above 4 mol/l, mostly in conjunction with impaired renal function.Conclusions Optimal peak and trough levels of netilmicin can be achieved by once daily dosing, adapted to gestational/postnatal age and renal function.     

Pharmacokinetics of cyclosporine A at a high-peak concentration of twice-daily infusion and oral administration in allogeneic haematopoietic stem cell transplantation

What is known and Objective: The most appropriate immunosuppressive strategy with calcineurin inhibitors for the prevention of acute graft‐versus‐host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) has not yet been established. To estimate the safety and efficacy of a new strategy, we investigated the pharmacokinetics of cyclosporine A (CyA) delivered by twice‐daily infusion and oral administration maintained with a peak level above 1000 ng/mL to keep 24 h area under the concentration–time curve (AUC0–24) higher than 10 000 ng·h/mL in 12 patients. Methods: Cyclosporine A was started as a twice‐daily infusion at 1·5 mg/kg and then orally administered at twice the infusion dose to maintain the trough blood concentration between 200 and 500 ng/mL, and with a peak level above 1000 ng/mL. Serial blood samples were collected at 0, 1, 2, 3, 5, 8 and 12 h after CyA dosing (C0, C1, C2, C3, C5, C8 and C12) on days 14–21 after transplantation and on days 7–14 after switching to oral administration, and the AUC was calculated. Results: In all patients, the AUC0–24 for both twice‐daily infusion and oral administration was higher than 10 000 ng·h/mL. Two close relationships were observed between AUC0–12 and the C3 for infusion and between AUC0–12 and the C8 for oral administration. None of the patients had grades 3–4 aGVHD or other serious complications. What is new and Conclusion: This strategy was well tolerated, and the C3 for twice‐daily infusion and the C8 for oral administration were the optimal points for monitoring of CyA concentration in the early phase of transplantation.     

Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonates

Background and objectives: Neonatal sepsis is frequently associated with pathological activation of the coagulation system, leading to microcirculatory derangement and multiple organ dysfunction syndrome (MODS). The key role in the pathogenesis of sepsis has been attributed to proinflammatory cytokines. These trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor‐dependent pathway of coagulation. Pentoxifylline (PTX), a methylxanthine derivative that is used in peripheral vascular disease, has the potential to modify inflammatory response. The current work was designed to evaluate the potential protective effects of PTX against sepsis‐induced microcirculatory derangement in Egyptian neonates. Methods: A double‐blind placebo‐controlled quasi‐randomized design was used. Thirty‐seven neonates with sepsis were randomly allocated into two groups. Seventeen patients were given PTX (5 mg/kg/h for 6 h; for 6 successive days). Twenty patients received equivalent volume of normal saline and represented the placebo group. Prothrombin time (PT), Activated partial thromboplastin time (APTT), fibrinogen, d ‐dimer, C‐reactive protein (CRP), complete blood count (CBC), also hemodynamic parameters comprising arterial blood pressure, heart rate, capillary refill and urinary output were assessed in both groups before and after treatment. Results: Coagulation parameters in the two groups showed no significant differences. However, a higher incidence of DIC was observed in the placebo group neonates. PTX significantly lowered the percentage of bleeding (P = 0·0128) and less frequent use of FFP was observed in the PTX group (35·53% in PTX group vs. 80% in placebo group, P = 0·003). Incidence of MODS was significantly lower (P = 0·037) and hospital stay duration of survivors was significantly shorter (P = 0·044) in the PTX treated‐infants. Conclusion: Pentoxifylline protects against sepsis‐induced microcirculatory derangement in neonates. It significantly lowered the incidence of bleeding and MODS and shortened the length of hospital stay.     

Population pharmacokinetics of enoxaparin in infants,children and adolescents during secondary thromboembolic prophylaxis: a cohort study

Summary. Background: Enoxaparin has been extensively studied in adults on its safety and efficacy during prevention of symptomatic thromboembolism when acute anticoagulation or secondary prevention is required as a result of venous thrombosis or stroke. In children, it is still used off‐label and little is known about the pharmacokinetics in children. Objectives: The aim of the present study was to evaluate whether a once‐ or twice‐daily dosing regimen would be feasible in children to achieve appropriate plasma levels of enoxaparin. Patients/methods: A population pharmacokinetic model was developed using anti‐factor (F)Xa activity data from 126 children (median age: 5.9 years) receiving enoxaparin either as a once‐ or twice‐daily dosing regimen. Results: A two‐compartment model was adequate for describing the enoxaparin kinetics. Body weight proved to be the most predictive covariate for clearance and central volume of distribution: clearance 15 mL h^?1 kg^?1, central volume of distribution 169 mL kg^?1, intercompartmental clearance 58 mL h^?1, peripheral volume of distribution 10 L and absorption rate 0.414 h^?1. Interindividual variability was found to be 54% for clearance and 42% for volume of distribution. Conclusion: The model is capable of describing all age groups and dosing levels of our population and predicts 12 h and 24 h enoxaparin activities sufficiently. According to our results, a once‐daily enoxaparin dosing regimen with frequent monitoring is feasible. In 53.2% of the patients the median 24 h trough level was above the desired range of 0.1 IU mL^?1 anti‐FXa activity for prophylaxis therapy.     

Relationship between amikacin blood concentration and ototoxicity in low birth weight infants

Amikacin (AMK) is used as empiric therapy for severe infections such as sepsis in low birth weight (LBW) infants. AMK administered once daily (OD) in adults is reported to be therapeutically effective and prevent side effects, however, evidence on AMK administration in LBW infants is limited, with no clear indications of effectiveness. We performed therapeutic drug monitoring analysis of 20 infants treated with AMK OD for severe infections such as bacteremia. Treatment effectiveness was admitted by the patients’ medical records, and side effects of renal dysfunction and ototoxicity were investigated. The mean gestational age was 30.4 ± 5 weeks and mean body weight (Bw) was 1280.2 ± 809.8 g. The mean AMK dose was 14.1 ± 2.6 mg/kg and mean administration period was 10.1 ± 4.1 days. Blood concentration was measured 6.3 ± 2.3 days after AMK administration; mean peak and trough concentrations were 29.1 ± 7.5 μg/mL and 7.6 ± 6.9 μg/mL, respectively. Additionally, therapeutic effect was observed in all patients, and no significant change in serum creatinine (CRE) concentration (a marker of renal dysfunction) was observed, suggesting no renal dysfunction. Ototoxicity was observed in 4 patients, 3 of whom had trough concentrations ≥10 μg/mL. When we categorized patients into two groups using a trough cut-off value of 10 μg/mL, no difference in AMK dose was observed. However, there were significant differences in peak concentration, Bw, volume of distribution and CRE. Our findings suggest AMK trough concentration ≥10 μg/mL significantly affects ototoxicity in neonates.     

Aminoglycoside pharmacokinetics in African-Americans with normal renal function

Objective: To compare aminoglycoside pharmaco?kinetics in African-Americans with normal renal function with published adult population values. Design: An Institutional Review Board approved concurrent study. Setting: The study was conducted at Howard University Hospital, Washington DC. Subjects: All subjects had serum creatinine levels of 1·5 mg/dl or less and were receiving aminoglycoside for suspected or documented Gram-negative infection, had no obvious underlying disease condition that could influence aminoglycoside pharmaco?kinetics and were aged 18 years or older. Main outcome measures: Volume of distribution (V_d), half-life ( t_1/2), elimination rate constant (K_e) and total body clearance ( Cl) were calculated using a one-compartment, open, linear pharmacokinetic model. Using an unpaired Student's t-test, the pharmaco?kinetic values of our patients were compared with general population values. Interventions: Patients receiving aminoglysides were identified by the pharmacist through the hospital's standard antibiotic order sheet. Twenty-five patients were enrolled after they met the inclusion criteria. Pharmacists made recommendations for dose change as part of standard of care when inappropriate doses were ordered. In collaboration with medical and nursing staff, the amount and time of dose administration, and steady-state peak and trough serum drug levels were stringently measured, documented on a data collection form and used to calculate pharmacokinetic values for our patients. The form was also used to document demographic information. Results: The following values were obtained: V_d 0·27±0·15 litres/kg, t_1/2 1·93±1·38 h, K_e 0·31±0·134/h (gentamicin), K_e 0·22±0·10/h (tobramycin), Cl 103·95±62·98 ml/kg/h (gentamicin) and Cl 118·96±84·83 ml/kg/h (tobramycin). These values are not significantly different from general population values. Following a mean tobramycin or gentamicin dose of 1·32±0·32 mg/kg ideal body weight (IBW)/dose or 1·11±0·33 mg/kg actual body weight (ABW)/dose every 8 h, patients achieved a mean peak and trough serum drug levels of 6·6±3·86 mg/litre and 1·03±0·68 mg/litre, respectively. Wide interpatient pharmacokinetic variability was also observed. Conclusions: We conclude that aminoglycoside pharmacokinetics in African-Americans seem to be consistent with the published general population values. Thus, initiating aminoglycoside regimens using population dosing guidelines appears to be appropriate. However, due to the observed wide interpatient pharmacokinetic variability, in?dividualized dosing is required with very close monitoring, to avoid or minimize toxicity.     

Effect of plasma uric acid on pharmacokinetics of cyclosporine A in living‐related renal transplant recipients and pharmacokinetic study in rats with experimental hyperuricaemia

Objectives: Renal transplant recipients are thought to have an increased risk of hyperuricaemia (HU); therefore, the effects of plasma uric acid (UA) on the pharmacokinetics (PK) of cyclosporine A (CyA), an immunosuppressant, in renal transplant recipients and experimental animals were investigated. Methods: An open‐label, non‐randomized, retrospective study was performed in renal transplant recipients. Data from 76 subjects who received a renal transplantation with CyA medication were included. We compared the PK of CyA of recipients showing a high UA level with the other recipients. In addition, PK studies were performed using hyperuricaemic‐model rats (HU rats) prepared by subcutaneous injection of the uricase inhibitor, potassium oxonate and intraperitoneal injection of UA. Results: The area under the blood concentration vs. time curve (AUC) up to 9 h, the blood level at 2 h after dose and peak level in high UA recipients (UA > 7·0 mg/dL) was significantly lower (about 10–16%) than that in the other recipients, although there were no differences in dose, and the trough blood level. On the contrary, there were no differences in PK parameters after intravenous administration of CyA between HU and control rats; however, AUC, peak level and bioavailability in HU rats (2·01 ± 0·56 μg h/mL, 0·47 ± 0·26 μg/mL and 0·186 ± 0·05, respectively) after oral administration were significantly lower than in the control animals (6·13 ± 0·97 μg h/mL, 0·82 ± 0·17 μg/mL and 0·458 ± 0·07 μg/mL, respectively). In addition, the absorptions of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in HU rats were significantly less (about 50% and 37%, respectively) than in the controls. Conclusions: The absorption of CyA was affected by plasma UA in transplant recipients and experimental rats. The contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in HU rats was significant. These results suggest that transplant recipients with high UA may have poor absorption of CyA.     

Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers

Background and objective: Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects. Methods: One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc^®) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, α‐hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared. Results and discussion: The area under the plasma concentration–time curve (AUC_0→∞), the maximum plasma concentration (C_max) and the elimination half‐life (T_1/2) of metoprolol and α‐hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0·05). The AUC_0→∞s of metoprolol were 443·7 ± 168·1, 995·6 ± 321·4 and 2545·3 ± 632·0 ng·h/mL, and the AUC_0→∞s of α‐hydroxymetoprolol were 1232·0 ± 311·2, 1344·0 ± 288·1 and 877·4 ± 103·4 ng·h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T_1/2 values of metoprolol were 2·7 ± 0·5, 3·2 ± 1·3 and 5·0 ± 1·1 h, while those of α‐hydroxymetoprolol were 5·4±1·5, 6·0 ± 1·4 and 10·5 ± 4·2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0·05). Conclusion: The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.     

Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation

What is known and objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12‐hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). Results: There were no significant differences in the dose‐adjusted area under the plasma concentration–time curve (AUC_0–12) and maximum plasma concentration (C_max) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co‐administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose‐adjusted AUC_0–12 and C_max of tacrolimus were associated with CYP3A5*3/*3 and co‐administration with lansoprazole. What is new and conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long‐term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.     

OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteers

Purpose: To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods: Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild‐type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography–mass spectrometry (LC–MS). Results: The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (C_max) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC_0–48) and area under the curve extrapolated to infinity (AUC_0–∞) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half‐life (t_1/2) and peak concentration times (T_max) values showed no difference between these groups. Conclusions: The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.     

Determination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokinetics

Objective: To develop a high performance liquid chromatography mass spectrometry (HPLC‐MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations. Methods: The GA in plasma was extracted with ethyl acetate, separated on a C₁₈ column with a mobile phase of methanol (5 mmol/L ammonium acetate)–water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469·5 for GA and m/z 455·6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively. Results: The calibration curve was linear over the range of 0·5–200 ng/mL (r = 0·9974). The limit of quantification for GA in plasma was 0·5 ng/mL, the recovery was 76·0–80·0%, and the inter‐ and intra‐day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t_1/2) 9·65 ± 3·54 h and 9·46 ± 2·85 h, the time to peak concentration (T_max) 10·95 ± 1·32 h and 11·00 ± 1·30 h, the peak concentration (C_max) 95·57 ± 43·06 ng/mL and 103·89 ± 49·24 ng/mL; the area under time‐concentration curve (AUC_0–48 and AUC_0–∞) 1281·84 ± 527·11 ng·h/mL and 1367·74 ± 563·27 ng·h/mL, 1314·32 ± 566·40 ng·h/mL and 1396·97 ± 630·06 ng·h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98·88 ± 12·98%. Conclusion: The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent.     

Kinetic profile of carbamazepine in an adult Portuguese outpatient population

Objective : The aim of our work was to define the kinetic profile of carbamazepine (CBZ), in order to improve on dosing schedules through a Bayesian approach. Method: Carbamazepine dose/steady-state trough concentrations data pairs and associated information were collected retrospectively on a population of adult epileptic patients. Results: Fifty patients (index population) with two or more available concentrations (total of 174 determinations) met our inclusion criteria. Patients were taking CBZ (200–1800 mg/day) in mono- or polytherapy regimens. The analysis assumed a one-compartimental model with first-order absorption and elimination. Due to the data source (only trough concentrations were measured as part of hospital routine), the volume of distribution was fixed at 1·19 l/kg. The final estimates for CL were: 0·075± 0·027 (mono- and polytherapy), 0·069±0·020 (monotherapy), and 0·106±0·037 l/h/kg (poly?therapy). In order to validate these results, we assessed their predictive capacity using 18 new patients (validation population), submitted to the same inclusion criteria and using Prediction-Error analysis. The results suggested a different CL value for our population compared to earlier published clearance values. The results also pointed to an increased metabolic rate associated with polytherapy. The prediction capacity of the optimization method derived from a Portuguese population made in an a priori evaluation indicated a low error (–0·04 μg/ml), close to the theoretical zero value. Conclusion: Our results provide specific data on CBZ disposition in a Portuguese population and given the wide variability in the literature values, our data may help improve dosing of CBZ in Portuguese patients.     

Effective plasma concentrations of itraconazole and its active metabolite for the treatment of pulmonary aspergillosis

BackgroundItraconazole (ITCZ) is used to treat pulmonary aspergillosis, but findings regarding the range of effective plasma concentrations are often contradictory. This study attempted to determine effective plasma concentrations of ITCZ and its active metabolite hydroxyitraconazole (OH-ITCZ) by retrospectively analyzing their relationships to clinical efficacy.MethodsThe study included 34 patients with pulmonary aspergillosis treated using ITCZ (mean age, 70 years). Each patient was treated with 200 mg ITCZ once daily (mean duration of treatment: 384 days). Plasma concentrations of ITCZ and OH-ITCZ at trough levels from 7 to 889 days after the start of treatment were determined using high-performance liquid chromatography. Clinical efficacy was assessed through the improvement clinical symptoms.ResultsFifteen patients were classified as effective group and the other 19 patients as non-effective group. Mean (±standard deviation) ITCZ trough plasma concentration was significantly higher in effective group (1254 ± 924 ng/mL) than in non-effective group (260 ± 296 ng/mL). Mean OH-ITCZ plasma concentration was significantly higher in effective group (1830 ± 1031 ng/mL) than in non-effective group (530 ± 592 ng/mL). Receiver operating characteristic curve analysis revealed the optimal cutoff for ITCZ trough plasma concentration was 517 ng/mL, and 86.7% of effective group showed concentrations exceeding this value. The optimal cutoff for total ITCZ + OH-ITCZ plasma concentration was 1025 ng/mL, and 93.3% of effective group showed a concentration exceeding this value.ConclusionsOur findings indicate that effective plasma concentration ranges for the treatment of pulmonary aspergillosis begin at an ITCZ trough plasma concentration of 500 ng/mL and a total ITCZ + OH-ITCZ plasma concentration of 1000 ng/mL.     

Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.

Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.     

Histamine 2 receptor antagonists vs intravenous proton pump inhibitors in a pediatric intensive care unit: a comparison of gastric pH

Purpose

The aim of this study was to assess gastric pH in critically ill pediatric patients receiving intravenous stress ulcer medication.

Materials and Methods

A prospective study was done in 48 patients with a gastric tube in place who were receiving either ranitidine or a proton pump inhibitor and no enteral nutrition. Daily peak and trough gastric pHs were measured.

Results

The median age was 7 years 5 months (range, 1 month to 19 years), the median weight was 31 kg (range, 3-130 kg), and the median pediatric risk of mortality 2 (PRISM2) score was 12.5 (range, 0-31). All patients were intubated and 8 received dialysis. The average trough pH was 4.4 ± 1.6 in the ranitidine group, 4.9 ± 1.8 in the once daily proton pump inhibitor group, and 5.0 ± 1.2 in the twice daily proton pump inhibitor group (P = .16). The average peak pH was 5.3 ± 1.8 in the ranitidine group, 5.9 ± 1.6 in the once daily proton pump inhibitor group, and 6.0 ± 1.0 in the twice daily proton pump inhibitor group (P = .06). Three (10%) of 28 trough pH measurements in the twice daily proton pump inhibitor group were more acidic than 4 vs 24 (40%) of 60 in the ranitidine group, and 22 (40%) of 56 in the once daily proton pump inhibitor group (P = .02). One (4%) of 27 peak pH measurements in the twice daily proton pump inhibitor group were more acidic than 4 vs 13 (20%) of 61 in the ranitidine group, and 9 (16%) of 56 in the once daily proton pump inhibitor group (P = .12). Three patients (6%; 95% confidence interval, 0.51%-16%) developed upper gastrointestinal bleeding, and 4 patients (8%; 95% confidence interval, 0%-13%) developed ventilator-acquired pneumonia.

Conclusions

Many critically ill pediatric patients receiving stress ulcer prophylaxis have a trough or peak gastric pH more acidic than 4.     

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers

Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography–tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post‐dose. Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC_0–∞ and C_max in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 μg·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 μg/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half‐life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (ΔC_glu11) in group C was significantly higher than that of group A (?1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.     

Doxycycline vs. levofloxacin in the treatment of community‐acquired pneumonia

Background: Community‐acquired pneumonia (CAP) affects 5–10 million adults annually in the United States with approximately 1·1 million hospitalizations. Current guidelines recommend fluoroquinolones as monotherapy for treatment of CAP in general medical wards and doxycycline monotherapy for outpatient therapy only. Fluoroquinolones are expensive and development of bacterial resistance to them has become a concern. Therefore, we studied whether doxycycline is as efficacious as levofloxacin in treatment of CAP in general medical wards. Methods: In this prospective double‐blinded trial, non‐pregnant adults with clinical and radiological evidence of pneumonia requiring hospitalization were enrolled. Patients who were septic, hypoxic requiring intubations, nursing home residents, diagnosed with severe hepatic or renal dysfunction, recently hospitalized or immunocompromised were excluded from the study. Subjects were randomly assigned to either i.v. levofloxacin 500 mg daily or doxycycline 100 mg twice daily. After discharge, patients were followed for 2 months. Results: There were 30 patients in the levofloxacin group and 35 patients in the doxycycline group. Groups were comparable in both clinical and laboratory profiles. Additionally, efficacy of treatment was not significantly different between the two groups (P = 0·844). Length of stay was 5·7 ± 2·05 days in the levofloxacin group and 4·0 ± 1·82 days in the doxycycline group (P < 0·0012). Failure rate was similar in both groups (P = 0·893). Total antibiotic cost was $122·07 ± 15·84 for levofloxacin and $64·98 ± 24·4 for doxycycline (P < 0·0001). Conclusions: Our study supports doxycycline as an effective and economical alternative therapy for levofloxacin in the empirical treatment of CAP in general medical wards.     

Population pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants: an update

What is known and objective: Optimal use of phenobarbital in the neonatal population requires information regarding the drug’s pharmacokinetics and the influence of various factors, such as different routes of administration, on the drug’s disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in neonates and infants. This study was conducted to establish the role of patient characteristics in estimating doses of phenobarbital for neonates and infants using routine therapeutic drug monitoring data. Methods: The population pharmacokinetics of phenobarbital was evaluated using 109 serum concentration measurements obtained from routine phenobarbital monitoring of 70 neonates and infants. The data were analysed using the non‐linear mixed effects model. A one‐compartment pharmacokinetic model with first‐order elimination was used. Covariates screened were current total bodyweight (TBW), gestational age, postnatal age (PNA), post‐conceptional age, gender and neonates‐infants clearance factor (serum concentration of phenobarbital; Conc). Results and discussion: The final pharmacokinetic parameters were CL/F (mL/h) = (5·95·TBW (kg) +1·41·PNA (weeks)) Conc (serum phenobarbital concentration >50 μg/mL)^?0·221,Vd/F (L) =1·01·TBW (kg), and F = 0·483 for oral administration and F = 1 was assumed for suppository. Conc^?0·221 is 1 for phenobarbital concentration <50 μg/mL. The important variables for predicting phenobarbital clearance in this study were TBW, PNA and Conc. Phenobarbital clearance increases proportionately with increasing TBW, and an older newborn was expected to have a higher rate of clearance than a younger newborn of equal bodyweight. Moreover, the clearance of phenobarbital decreased nonlinearly with increasing serum concentration of phenobarbital >50 μg/mL (Conc^?0·221). What is new and conclusion: We developed a new model for neonate and infant dosing of phenobarbital with good predictive performance. Clinical application of our model should permit more accurate selection of initial and maintenance doses to achieve target phenobarbital concentrations in Japanese neonates and infants, thereby enabling the clinician to achieve the desired therapeutic effect. A similar approach can be used to validate our model for use in other neonate and infant populations.