Area Under The Concentration-versus-time Curve Research Articles

Challenges associated with test dose pharmacokinetic predictions of high dose melphalan exposure in patients with multiple myeloma

AimTo evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE).MethodsA prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35–71) years using a 20 mg/m2 test dose administered 1–3 days prior to HDM (predominantly 180 mg/m2). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann–Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined.ResultsPredicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p < 0.005). Test dose administration within 15 min of reconstitution (n = 5) was associated with significantly lower PE than administration times of 16–60 min (n = 22), p < 0.05. Test and HDM infusion concentrations were lower in patients with large PE (> ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively).ConclusionTest dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation.

Reduced Enterohepatic Recirculation of Mycophenolate and Lower Blood Concentrations Are Associated with the Stool Bacterial Microbiome after Hematopoietic Cell Transplantation

Mycophenolate mofetil (MMF) is an important immunosuppressant used after allogeneic hematopoietic cell transplantation (HCT). MMF has a narrow therapeutic index, and blood concentrations of mycophenolic acid (MPA), the active component of MMF, are highly variable. Low MPA concentrations are associated with the risk of graft-versus-host disease (GVHD), whereas high concentrations are associated with toxicity. Reasons for variability are not well known and may include the presence of β-glucuronidase-producing bacteria in the gastrointestinal tract, which enhance MPA enterohepatic recirculation (EHR) by transforming MPA metabolites formed in the liver back to MPA. This study was conducted to determine whether individuals with high MPA EHR have a greater abundance of β-glucuronidase-producing bacteria in their stool and higher MPA concentrations compared with those with low EHR. We conducted a pharmacomicrobiomics study in 20 adult HCT recipients receiving a myeloablative or reduced-intensity preparative regimen. Participants received MMF 1 g i.v. every 8 hours with tacrolimus. Intensive pharmacokinetic sampling of MMF was conducted before hospital discharge; total MPA, MPA glucuronide (MPAG), and acyl-glucuronide metabolite (acylMPAG) were measured. EHR was defined as the ratio of MPA area under the concentration-versus-time curve (AUC)4-8 to MPA AUC0-8. Differences in stool microbiome diversity and composition, determined by shotgun metagenomic sequencing, were compared above and below the median EHR (22%; range, 5% to 44%). The median EHR was 12% in the low EHR group and 29% in the high EHR group. MPA troughs, MPA AUC4-8, and acyl-glucuronide metabolite (acylMPAG) AUC4-8/AUC0-8 ratio were greater in the high EHR group compared with the low EHR group (1.53 μg/mL versus .28 μg/mL [P=.0001], 7.33 hour·μg/mL versus 1.79 hour·μg/mL [P=.0003], and .33 hour·μg/mL versus .24 hour·μg/mL [P=.0007], respectively). MPA AUC0-8 was greater in the high EHR group than in the low EHR group, and the difference trended toward significance (22.8 hour·μg/mL versus 15.3 hour·μg/mL; P=.06). Bacteroides vulgatus, Bacteroides stercoris, and Bacteroides thetaiotaomicron were 1.2- to 2.4-fold more abundant (P=.039, .024, and .046, respectively) in the high EHR group. MPA EHR was positively correlated with B. vulgatus (⍴=.58; P ≤ .01) and B. thetaiotaomicron (⍴=.46; P < .05) and negatively correlated with Blautia hydrogenotrophica (⍴=-.53; P < .05). Therapeutic MPA troughs were achieved in 80% of patients in the high EHR group but in no patients in the low EHR group. There was a trend toward differences in MPA AUC0-8 and MPA concentration at steady-state (μg/mL) between the high EHR group versus the low EHR group (P=.06). MPA EHR was variable. Patients with high MPA EHR had greater abundance of Bacteroides species in stool and higher MPA exposure compared with patients with low MPA EHR. Therefore, Bacteroides may be protective against poor outcomes, such as graft-versus-host disease, in some patients but may increase the risk of MPA adverse effects in others. These data need to be confirmed and studied after oral MMF therapy.

Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer.

To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events. Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUVmax) variation (ΔSUVmax) after 1 cycle using [18F]-fluorodeoxyglucose (FDG) PET. Early poor responders (ΔSUVmax < 70%) also received bevacizumab from cycle 3 to cycle 6. Sources of interindividual variability in pharmacokinetics of both antibodies were studied by population compartment modelling. Exposure as assessed by area under the concentration-versus-time curve (AUC) was compared between responders and non-responders and between patients experiencing specific adverse events or not. A two-compartment model described the pharmacokinetics of both antibodies satisfactorily. Their central volume of distributions (Vc) increased with body surface area and their elimination half-lives were shorter (~14days) than previously reported (~26-28days). There was a time-dependent increase in trastuzumab Vc, positively correlated to baseline SUVmax. Bevacizumab elimination rate (k10) was positively correlated with ΔSUVmax measured at the end of the first cycle. Bevacizumab had no significantly influence on trastuzumab pharmacokinetics. No relationship between exposure and clinical response or occurrence of adverse events was found. Tumour uptake as assessed by SUVmax influences the pharmacokinetics of bevacizumab and trastuzumab. In early-stage breast cancer, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than those previously reported in more advanced disease.

Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis.

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (Cmax) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) Cmax was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC0-24) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a Cmax of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

A Multicentre Study Investigating the Pharmacokinetics and Pharmacodynamics of Busulphan When Combined with Melphalan As Conditioning in Adult Autologous Transplant Recipients

Busulfan (Bu) is an alkylating agent commonly used in conditioning regimens prior to allogeneic stem cell transplantation (SCT). Whilst systemic drug exposure is thought to be critical for efficacy and safety of this agent (Kletzel et al. 2006; Bartelink et al. 2009; Andersson et al. 2002), there is a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) evidence-based guidelines outlining how best to balance these potentially competing outcomes. In this study Bu PK was investigated in the setting of IV Bu-melphalan (mel) autologous SCT, with the primary intention of establishing factors influencing Bu exposure and how effectively PK assessment can be used to achieve desirable drug exposure. PD analysis was also performed to establish the effect of drug exposure on transplant-related toxicity.Sixty-four adult patients with haematological malignancies were prospectively enrolled prior to IV Bu-mel autologous SCT. PK analysis was performed in all patients on a "test" dose of Bu (1.6mg/kg, ie. 50% of a therapeutic dose) on day-7 based on actual body weight (ABW) (n=38) or adjusted ideal body weight (AIBW; n=24) where AIBW (kg) = Ideal body weight + [0.25 x (ABW- IBW)]). All patients subsequently received a second 1.6mg/kg dose on day-6. Thereafter, 27 patients received a further three ’therapeutic’ daily doses of 3.2mg/kg on days -5 to -3 irrespective of PK results whist the remaining 37 patients received a modified dose, guided by the results of the initial PK results, targeting a subsequent Bu exposure, expressed as the area-under-the-concentration-versus- time curve (AUC), between 4000-5000umol.min/day (4000 in 2, 4500 in 14, 4800 in 4 and 5000 umol.min/day in 17) the lower ranges targeted in older patients with less aggressive disease. All patients had repeat PK analysis on day-5. Pre−transplant factors including age, weight, body mass index (BMI) and renal function were evaluated for their effect on the relationship between Bu dose and AUC; a multivariate analysis was performed on all covariates that were significant (p<0.05) in a univariate analysis.The mean Bu dose for patients receiving PK-guided dosing was 3.4mg/kg (range 2.6-4.8 mg/kg) with the mean AUCs in the target groups of 4000-4500 and 4800-5000 umol.min/day being 4821 (3639-5457) and 5142 (4138-6157) umol.min/day respectively; the mean AUC for the non-adjusted-dose cohort was 4785umol.min/day (3251-6305umol.min/day); (p=0.16). All but one patient in the PK-guided group (36/37) vs 22/27 (81%) in the non-adjusted group (p=0.03) achieved AUCs within the 3500-6000umol.min/day range, which has been found to be safe and effective in previous studies (Clemmons et al. 2015). Of the five patients who did not achieve this target, 3 achieved AUCs below 3500umol.min/day and 2 greater than 6000umol.min/day.Day -5 dose adjustments (from 3.2mg/kg) were suggested for 92% (34/37) of eligible patients and implemented in 87% (32/37) patients. These consisted of a Bu dose less than 3.2mg/kg (2.6-3.1mg/kg) in 8 patients which resulted in a mean AUC 5182umol.min/day (3904-6157umol.min/day); 38% of these patients achieved their target AUC (+/-10%). Five patients received an unchanged Bu dose of 3.2mg/kg achieving a mean AUC of 4906umol.min/day (4302- 5717umol.min/day) of which two were within 10% of their target AUC. Twenty-four patients received an increase dose (3.3-4.8mg/kg) and achieved a mean 4954umol.min/day (3639-5890umol.min/day) 45% achieved their target AUC (+/-10%). The mean variance from the target was 11% (0-30%). Using ABW or AIBW did not impact on this variance (mean 10% vs 12% respectively). Doses were frequently reduced (51% in the dose-adjusted cohort, mean of 15%) from the suggested dose based on day-7 AUC as it was observed early that the mean day-5 AUCs, in both cohorts, were higher than anticipated for the dose prescribed (mean 11%, -22 - 31%).Multivariate analysis demonstrated actual weight as the only independent variable impacting the relationship between Bu dose and AUC; higher body weight was associated with lower AUCs (p=0.02) relative to Bu dose. No correlation between AUC and the occurrence of grade 3 or greater transplant related toxicities such as mucositis (based on number of days requiring total parental nutrition) or hepatotoxicity was observed.PK-directed Bu dosing may be of benefit in achieving a target level of drug exposure, but larger studies are needed to determine the clinical significance of this strategy. DisclosuresHarrison:AbbVie: Research Funding; Janssen Cilag: Research Funding, Speakers Bureau.

Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment.

Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIV-uninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, ≥90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (Cmax) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUCinf) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV Cmax and AUCinf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens.

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

Achievement of a busulfan area-under-the-concentration versus time curve (AUC) of 900 to 1500 μM·min is associated with improved hematopoietic stem cell transplant (HSCT) outcomes. Multiple pediatric busulfan dosing guidelines aim to achieve this target. The authors' objective was to describe the AUCs achieved after simulated dosing using available pediatric i.v. busulfan dosing guidelines. The health records of children who received i.v. busulfan for HSCT conditioning at The Hospital for Sick Children were reviewed. Busulfan AUCs were calculated for each patient based on plasma busulfan concentrations using either a 1-compartment model or a validated limited-sampling strategy. Published pediatric busulfan dosing guidelines were identified. Initial busulfan doses were determined for all patients using each dosing guideline and total body weight (TBW). For overweight patients (TBW-to-ideal body weight [IBW] ≥ 1.25), initial busulfan doses were also determined using IBW and adjusted IBW (IBWadj). The resulting AUCs were simulated. The proportion of subjects (TBW/IBW < 1.25, TBW/IBW ≥ 1.25, and infants) with an AUC within target (900 to 1500 μM·min) after dosing simulation with each guideline was compared. One hundred eleven children (mean age, 6.2 years [SD, ±5.2]) who received i.v. busulfan were included. When dosing with each of the 12 i.v. busulfan dosing guidelines identified was simulated using TBW in 97 non-overweight patients, the proportion of patients with an AUC within the target range varied from 51% to 74% and from 45% to 64% in infants. Use of IBW or IBWadj to calculate initial busulfan doses in overweight children improved the performance of most guidelines. Current busulfan dosing guidelines vary in their ability to achieve AUCs within the target range. For children who are not overweight, we recommend 1 of 3 high-performing guidelines that allow individualization of the target busulfan AUC. Use of either IBW or IBWadj in overweight children improves the performance of most guidelines. Regardless of the guideline used, therapeutic drug monitoring is essential to verify achievement of the target AUC.

[Use of limited sampling strategy for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients].

To establish a formula for estimating area under the concentration-versus-time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric-coated mycophenolate sodium (EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose (C0), 0.5 (C0.5), 1.0 (C1), 1.5 (C1.5), 2.0 (C2), 3.0 (C3), 4.0 (C4), 6.0 (C6), 8.0 (C8) and 12.0 (C12) h post-dose respectively. Pharmacokinetic parameters of MPA (C0, C12, Cmax, Tmax, AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus (Tac) group or cyclosporin A (CsA) group were established by multiple stepwise regression analysis. There were variable MPA AUC0-12 h levels between 14 and 67 mg×h/L (mean: 37 ± 14). The MPA trough level (C0) had no correlations with MPA AUC0-12 h (r(2) = 0.090) . The simplified MPA AUC formula for Tac group was AUC = 5.678+1.718×C4+2.853×C6+1.812×C8+3.413×C12 with four sampling points (C4, C6, C8, C12). Estimated AUC with the formula had correlations with AUC0-12 h (r(2) = 0.890). The mean absolute predict error (APE) was 3.45% (0.41%-24.71%) and the proportion of APE above 15% stood at 11.1% (2/18) . In CsA group, the simplified MPA AUC formula was AUC = 7.072+1.525×C3+1.558×C4+ 1.573×C6+2.285×C8. The correlation was r(2) = 0.952, mean APE was 6.50% (0.02%-12.91%) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12 h by Bland-Altman analysis. The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12 h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.

P-Glycoprotein and Breast Cancer Resistance Protein Affect Disposition of Tandutinib, A Tyrosine Kinase Inhibitor

Tandutinib is a tyrosine kinase inhibitor under investigation for the treatment of solid and hematological tumors. We evaluated efflux transporter substrate specificity of tandutinib in Caco-2 cells, and the role of efflux transporters in the disposition of tandutinib in rats and efflux transporter knock-out mice. These studies demonstrated that tandutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in Caco-2 cells. In rats, administration of GF120918, before treatment with tandutinib orally resulted in approximately a seven-fold increase in the mean plasma area under the concentration-versus-time curve (AUC) compared to the vehicle control group. In mice, after intravenous administration of tandutinib, the mean plasma AUC values in the Bcrp1(-/-) mice and Mdr1a/b(-/-) mice was 1.53- and 1.20-fold greater than that of the wild type (WT) mice, respectively. After oral administration, the drug exposure in Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) mice was higher than in the WT mice. The brain to plasma exposure ratio (B/P) of tandutinib in Mdr1a/b(-/-) mice increased by 2- to 3-fold over that in the WT mice. There was a 13-fold increase in B/P in Mdr1a/b(-/-)/Bcrp1(-/-) mice. This finding illustrates that P-gp and Bcrp play a role in oral absorption, systemic clearance, and brain penetration of tandutinib in the rodents. P-gp affected oral absorption and brain penetration of tandutinib to a greater extent than Bcrp, but Bcrp contribution to systemic clearance of tandutinib was greater than P-gp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clinically.

Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease

Subcutaneous administration of intravenous immunoglobulin G (IgG) preparations provides an additional level of patient convenience and more options for patients with poor venous access or a history of intravenous IgG reactions. An open-label, pharmacokinetic trial (n = 32) determined the non-inferiority of the subcutaneous versus intravenous route of 10% caprylate/chromatography purified human immune globulin intravenous (IGIV-C; Gamunex®) administration by comparing the steady-state area under the concentration-versus-time curve (AUC) of total plasma IgG in patients with primary immunodeficiency disease. Patients on stable IGIV-C received two intravenous infusions (administered 3 or 4 weeks apart). Seven to 10 days after the second intravenous infusion, all patients switched to a weekly infusion of subcutaneous IGIV-C, with the dose equal to 137% of the previous weekly equivalent intravenous dose, for up to 24 weeks. Samples for pharmacokinetic analysis were collected during steady state for intravenous and subcutaneous IGIV-C treatments. The AUC(0-) τ geometric least-squares mean ratio was 0·89 (90% confidence interval, 0·86-0·92) and met the criteria for non-inferiority. The overall mean steady-state trough concentration of plasma total IgG with subcutaneous IGIV-C was 11·4 mg/ml, 18·8% higher than intravenous IGIV-C (9·6 mg/ml). Subcutaneous IGIV-C was safe and well tolerated. Subcutaneous IGIV-C infusion-site reactions were generally mild/moderate and the incidence decreased over time. No serious bacterial infections were reported. Weekly subcutaneous IGIV-C infusion using 137% of the weekly equivalent intravenous immunoglobulin dose provides an AUC comparable to intravenous administration, thus allowing patients to maintain the same IgG preparation/formulation if switching between intravenous and subcutaneous infusions.

Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring

AbstractWe prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 μMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate.

Stereoselective pharmacokinetics of ketamine and norketamine after constant rate infusion of a subanesthetic dose of racemic ketamine or S-ketamine in Shetland ponies

To evaluate pharmacokinetics of ketamine and norketamine enantiomers after constant rate infusion (CRI) of a subanesthetic dose of racemic ketamine or S-ketamine in ponies. Five 6-year-old Shetland pony geldings that weighed between 101 and 152 kg. In a crossover study, each pony received a CRI of racemic ketamine (loading dose, 0.6 mg/kg; CRI, 0.02 mg/kg/min) and S-ketamine (loading dose, 0.3 mg/kg; CRI, 0.01 mg/kg/min), with a 1-month interval between treatments. Arterial blood samples were collected before and at 5, 15, 30, 45, and 60 minutes during drug administration and at 5, 10, 30, and 60 minutes after discontinuing the CRI. Plasma ketamine and norketamine enantiomers were quantified by use of capillary electrophoresis. Individual R-ketamine and S-ketamine concentration-versus-time curves were analyzed by use of a monocompartmental model. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating the area under the concentration-versus-time curve (AUC), maximum concentration (Cmax), and time until Cmax. Plasma concentrations of S-ketamine decreased and biodegradation products increased more rapidly after S-ketamine CRI, compared with results after racemic ketamine CRI. The R-norketamine was eliminated faster than was the S-norketamine. Significant differences between treatments were found for the AUC of S-ketamine and within the racemic ketamine CRI for the AUC and Cmax of norketamine isomers. CRI of S-ketamine may be preferable over CRI of racemic ketamine in standing equids because the S-enantiomer was eliminated faster when infused alone instead of as part of a racemic mixture.

Phase I clinical and pharmacokinetic study of the glucose-conjugated cytotoxic agent d-19575 (glufosfamide) in patients with solid tumors

D-19575 (glufosfamide: β-D-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to β-D-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of D-19575 in Japanese patients with advanced solid tumors Patients were treated with escalating doses of D-19575 administered by a two-step (fast-slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1-11) at D-19575 doses of 3,200, 4,500, or 6,000 mg/m(2). Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of D-19575 was 6,000 mg/m(2), at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for >5 months, and eight patients achieved disease stabilization. Our results show that D-19575 can be safely administered by infusion over 6 h at 4,500 mg/m(2) every 3 weeks. The safety profile and potential antitumor activity of D-19575 show that phase II studies of this drug are warranted.

Effect of omeprazole on the plasma concentrations of indinavir when administered alone and in combination with ritonavir

The effects of omeprazole on indinavir when administered alone or in combination with ritonavir were evaluated. Fourteen men and women age 18-55 years not infected with human immunodeficiency virus who met study qualifications were randomized to receive placebo, 20 mg of omeprazole, or 40 mg of omeprazole daily. After seven days, the single-dose pharmacokinetic profile of an 800-mg dose of indinavir alone or in combination with 200 mg of ritonavir was evaluated. Study participants received each of four study regimens in one of four randomly assigned orders. Blood samples were collected, and plasma indinavir and ritonavir concentrations were analyzed using high-performance liquid chromatography. The coadministration of 20 or 40 mg of omeprazole with indinavir significantly reduced the mean indinavir area under the concentration-versus-time curve (AUC) from 30.0 mg x hr/L (95% confidence interval [CI], 21.9-41.1 mg x hr/L) to 19.7 mg x hr/L (95% CI, 14.6-26.8 mg x hr/L) or 16.0 mg x hr/L (95% CI, 11.8-21.7 mg x hr/L), respectively (p < 0.002). The addition of 200 mg of ritonavir to 800 mg of indinavir in combination with 40 mg of omeprazole significantly increased the mean indinavir AUC from 30.0 mg x hr/L (95% CI, 21.9-41.1 mg x hr/L) to 46.6 mg x hr/L (95% CI, 34.0-63.8 mg x hr/L), but it did not significantly affect mean omeprazole concentrations (p < or = 0.02). The AUC of indinavir was substantially decreased in healthy volunteers who received omeprazole 20 or 40 mg daily for seven days before the administration of a single 800-mg dose of indinavir. Concomitant administration of ritonavir 200 mg with indinavir in participants receiving omeprazole led to a significant increase in the AUC of indinavir.

Chronopharmacokinetics of Imipenem in the Rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10∶00, 16∶00, 22∶00, or 04∶00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were Cmax, Tmax, elimination half‐life (t1/2), area under the concentration‐versus‐time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of Cmax (49%), Tmax (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra‐individual variability.

Properties of pramlintide and insulin upon mixing

The pharmacokinetics, pharmacodynamics, and safety of pramlintide and various insulin formulations in patients with type 1 diabetes mellitus (DM) when given as separate injections or mixed in the same syringe before injection were studied. In two randomized, open-label, placebo-controlled, five-period-crossover studies, patients with type 1 DM received preprandial injections of pramlintide, short-acting insulin, and long-acting insulin administered either by separate injections or after mixing in various combinations. Serum free insulin and plasma glucose concentrations were measured for 10 hours and plasma pramlintide concentrations for 5 hours after injection. Blood samples were collected from a total of 51 patients. All treatments involving mixtures were comparable to separate injections with respect to the area under the concentration-versus-time curve (AUC) and the maximum concentration (Cmax) of serum free insulin. There were some minor differences in the AUC and Cmax of pramlintide. No injection-site reactions or other unexpected adverse events were observed. Mixing pramlintide with short- or long-acting insulin in the same syringe before subcutaneous injection did not affect the pharmacodynamics of glucose or the pharmacokinetics of insulin or pramlintide in a clinically significant manner.

Overlap coefficient for assessing the similarity of pharmacokinetic data between ethnically different populations

We developed a method to assess the similarity of pharmacokinetic data between ethnically different populations. An evaluation of confidence intervals for the mean difference in pharmacokinetic parameters, such as area under the concentration-versus-time curve (AUC), between populations is often used. We propose the use of the overlap coefficient (OC), which represents the proportion of overlap between two probability distributions, as a measure of the similarity between distributions. We considered five OC estimators--two parametric ones and three nonparametric ones. Simulation studies were conducted to compare the performance of the five OC estimators and their bootstrap confidence intervals. Results showed that nonparametric estimators with fixed-bandwidth kernel density estimation had a smaller mean squared error in almost all situations, and their coverage probabilities were close to the nominal level. The proposed method was applied to pharmacokinetic data from a bridging study of a combination therapy for metastatic colorectal cancer patients in the USA and Japan. From the analyses of this study, it was suggested that the distributions of the logarithmically transformed AUC for leucovorin and 5-fluorouracil were similar between the two populations.

Effect of glomerular filtration rate on clearance and myelotoxicity of carboplatin in cats with tumors

To characterize the pharmacokinetic disposition of carboplatin and determine whether glomerular filtration rate (GFR) could be used to predict carboplatin clearance and myelotoxic effects in cats with tumors. 10 cats with tumors. Glomerular filtration rate was assessed in each cat by monitoring plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Each cat received carboplatin (200 mg/m2 of body surface area) administered as an IV bolus. Plasma platinum concentrations were measured via atomic absorption spectrophotometry, and pharmacokinetic analysis was performed. A CBC was performed weekly for each cat, and the correlation between the area under the concentration-versus-time curve (AUC) and the severity of myelosuppression was calculated. Least squares regression analysis was performed to determine whether GFR could be used to predict plasma platinum clearance (ClPt). For all cats, AUC measurements ranged from 0.99 to 4.30 min x mg x mL(-1). Neutrophil concentration nadirs were detected 1 to 3 weeks after treatment and ranged from 200 to 8,000 cells/microl. The absolute neutrophil concentration at the nadir was inversely correlated with AUC. The ClPt was predicted by use of GFR measurements (ClPt = 2.60 x GFR). A carboplatin dose prescription model was derived involving AUC, estimated ClPt, and body weight in kilograms (BWkg), in which dose = AUC x 2.60(GFR) x BWkg. In cats, an individualized prescription strategy for carboplatin administration based on a targeted AUC and determination of GFR might more uniformly predict myelosuppression than that predicted by conventional dosing based on body surface area.

Red wine decreases cyclosporine bioavailability

BackgroundMany commonly ingested substances such as grapefruit juice and Hypericum perforatum (St John's wort) have been found to interact with important therapeutic agents such as cyclosporine (INN, ciclosporin). The mechanism for these interactions is thought to involve modulation of the activity of the drug‐metabolizing enzyme cytochrome P4503A4 (CYP3A4) and/or the drug transport protein P‐glycoprotein. In vitro data suggest that red wine may interact with CYP3A4 substrates such as cyclosporine.MethodsWe conducted a randomized, 2‐way crossover study of 12 healthy individuals. Subjects received a single 8‐mg/kg dose of oral cyclosporine with water (control) and with 12 oz of red wine (Blackstone Merlot 1996; Blackstone Winery, Graton, Calif). Whole blood was analyzed for cyclosporine and 6 metabolites by specific fluorescence polarization immunoassay and tandem liquid chromatography‐mass spectrometry. Blood levels of cyclosporine were compared between the 2 arms.ResultsRed wine caused a 50% increase in the oral clearance of cyclosporine. Systemic exposure as measured by the area under the concentration‐versus‐time curve (AUC) and peak concentration (Cmax) were significantly decreased by red wine. However, half‐life was not affected, suggesting that red wine decreased cyclosporine absorption. In vitro, the solubility of cyclosporine in red wine appeared to be lower than in water.ConclusionsAdministration of cyclosporine with red wine causes a significant decrease in cyclosporine exposure. Because cyclosporine is a narrow therapeutic range compound, caution may be warranted with concomitant intake of red wine and cyclosporine.Clinical Pharmacology &amp; Therapeutics (2001) 70, 462–467; doi: 10.1016/S0009‐9236(01)70992‐7

Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.