Pharmacokinetics of a new microemulsion formulation of cyclosporin A (Neoral) in young patients after renal transplantation

Pharmacokinetics of the new galenic formulation of cyclosporin A, Neoral, (Sandoz) was examined in 12 stable young patients after renal transplantation. Six of these patients were tested before and 4 weeks after switching from the standard formulation Sandimmun to Neoral. No significant changes were observed in trough levels, t_max, C_max, and AUC_0–12h, but the absorption rate constant (K_a) increased (P=0.003). Glomerular filtration rate, as assessed by inulin clearance, increased by more than 10% in three patients and decreased in two, and was usually associated with a respective drop and rise in C_max and AUC_0–12h of cyclosporin A. The large interindividual variability in the response to the conversion to the new formulation points to a need for close monitoring of cyclosporin A trough levels and renal function after switching from Sandimmun to Neoral in this age group in order to avoid nephrotoxicity.     

A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open‐label, randomized, two‐period (14 days per period), two‐sequence, crossover and steady‐state pharmacokinetic study was undertaken to compare twice‐daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC_0–12h and peak concentration (C_max) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97–108%, p = 0.486) for AUC_0–12h and 1.09 (90% CI 101–118%, p = 0.057) for C_max. Mean (SD) C₀ was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.     

A randomized,crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open‐label, randomized, two‐period (14 d per period), two‐sequence, crossover, steady‐state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre‐study twice‐daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC_0–12 h, C_max, and C₁₂ with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose‐normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose‐normalized AUC_0–12 h, C₁₂, C_max, or t_max between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose‐normalized AUC_0–12 h and C₁₂ with generic vs. reference tacrolimus were within 80–125% for all subpopulations, as were 90% CIs for C_max other than for females, African Americans, and non‐diabetics, which is not unexpected given the wide variability of tacrolimus C_max and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations.     

Interindividual Variation of Maximal Blood Levels of Tacrolimus After Its Oral Administration in Hematopoietic Cell Transplant Recipients

We investigated the pharmacokinetics of oral tacrolimus in 31 hematopoietic cell transplant recipients, identifying 2 subgroups based on the differences between C₀ (trough) and C_max (maximal) levels: group A (n = 21; 68%) with a C_max-C₀ value of <10 ng/mL, and group B (n = 10; 32%) with a C_max-C₀ value of ≥10 ng/mL. Although the C₀ and C₁₂ values were not significantly different between the 2 groups, the mean area under the concentration curve for 12 hours (AUC_0–12) was significantly greater in group B than group A (200.9 ± 36.3 vs 155.1 ± 43.1 ng · h/mL; P < .05), and the mean half-life was significantly shorter in group B than group A (13.55 ± 6.70 vs 18.17 ± 6.30 hours; P < .05). Thus after the oral administration of tacrolimus, we observed a notably high AUC due to high peak level, which we were unable to predict simply by measuring the trough level. A pharmacokinetic analysis of each patient was essential to optimize the oral tacrolimus dose.     

Effect of tangerine juice on cyclosporine levels in renal transplant children

The aim of our study was to investigate the effect of tangerine juice on the pharmacokinetics of cyclosporine A (CsA), in children who had received a renal transplant. This placebo-controlled study was done on ten kidney transplant recipients with stable cyclosporine trough levels who received either tangerine (Unshio Satsuma) juice or water. Patients were given their morning doses of CsA and then 250 ml water or the juice, and 12 h, investigations of the pharmacokinetics (PK) were performed. The main outcome measures were peak concentration and time to peak and area under the concentration–time curve. Administration of CsA with tangerine juice compared with water did not increase significantly the area under the whole-blood concentration versus time curve from 0–12 h (AUC_0–12) of CsA, (tangerine juice 2,797 ± 1,361 (P = 0.5); water 3,053 ± 1,532). Co-administration of tangerine juice with CsA compared with water had no significant effects on the AUC_0–12, peak concentration (C_max) or time to C_max (t_max) of the CsA in pediatric renal transplantation.     

Pharmacokinetics of oral levonorgestrel and ethinylestradiol in women after Roux-en-Y gastric bypass surgery

BackgroundMost patients undergoing Roux-en-Y gastric bypass (RYGB) are women in reproductive age. It is not known if bariatric surgery affects the pharmacokinetics of oral contraceptives.ObjectivesThe primary objective was to evaluate ethinylestradiol (EE) and levonorgestrel (LNG) absorption in women undergoing RYGB, compared with nonoperated controls matched by age and body mass index (BMI). A secondary objective was to assess whether the time since surgery and BMI in the postoperative period influenced the absorption parameters.SettingUniversity hospital, Brazil.MethodsThis study was designed to compare the maximum plasma concentration (C_max), the time to the peak plasma level (T_max), the area under the curve (AUC_0–8 and AUC_0–∞) after a single dose of a combined oral contraceptive with 0.03 mg EE and 0.15 mg LNG among 20 women after RYGB and 20 controls. Blood samples were obtained for 8 hours.ResultsThe mean LNG AUC_0–8 and LNG AUC_0–∞ were higher in RYGB group (P = .048 and P = .004, respectively). We found a positive correlation for LNG AUC_0–8 (P = .045) and AUC_0–∞ (P = .004) and the time since surgery, and we found a negative correlation for LNG C_max (P = .018), AUC_0–8 (P = .003), and AUC_0–∞ (P = .001) and BMI.ConclusionNo significant differences were found in oral EE pharmacokinetics. The operated group showed higher mean LNG AUC_0–8 and AUC_0–∞ but it was not considered clinically significant. The present study suggests that RYGB may not affect EE and LNG absorption.     

Conversion from twice- to once-daily tacrolimus in pediatric kidney recipients: a pharmacokinetic and bioequivalence study

Background

The objectives of this study were to investigate pharmacokinetic and pharmacogenetic parameters during the conversion on a 1:1 (mg:mg) basis from a twice-daily (Prograf) to once-daily (Advagraf) tacrolimus formulation in pediatric kidney transplant recipients.

Methods

Twenty-four-hour pharmacokinetic profiles were analyzed before and after conversion in 19 stable renal transplant recipients (age 7–19 years). Tacrolimus pharmacokinetic parameters [area under the concentration-time curve (AUC_0–24), minimum whole-blood concentration (C_min), maximum whole-blood concentration (C_max), and time to achieve maximum whole-blood concentration (t_max)] were compared between Tac formulations and between CYP3A5 and MDR1 genotypes after dose normalization.

Results

Both AUC_0–24 and C_min decreased after conversion (223.3 to 197.5 ng.h/ml and 6.5 to 5.6 ng/ml; p?=?0.03 and 0.01, respectively). However, the ratio of the least square means (LSM) for AUC_0–24 was 90.8 %, with 90 % CI limits of 85.3 to 96.7 %, falling within bioequivalence limits. The CYP3A5 genotype influences the dose-normalized C_min with the twice-daily formulation only.

Conclusions

Both tacrolimus formulations are bioequivalent in pediatric renal recipients. However, we observed a decrease in AUC_0–24 and C_min after the conversion, requiring close pharmacokinetic monitoring during the conversion period.     

A comparative study of FK506 granules and capsules in renal transplant recipients

Nine renal transplant recipients in stable systemic condition on FK506 capsules were converted to FK506 granules in order to investigate the safety, efficacy, and pharmacokinetics of the granular formulation of FK506. The study period for the administration of FK506 granules was 4 weeks, and in principle, the oral dose was the same as that of the FK506 capsules. Renal graft function remained stable and no rejection signs were noticed while the patients were taking the granules. The area under the blood concentration-time curve (AUC), the maximum blood level (C_max), and the time to reach C_max (T_max) after FK506 capsules and FK506 granules were, respectively, 93.1 ± 66.4 and 97.0 ± 89.1 ng · h/ml (P = 0.81), 12.7 ± 7.1 and 15.2 ± 11.7 ng/ml (P = 0.39), and 2.0 ± 1.7 and 1.3 ± 0.6 h (P = 0.29). The mean trough blood level during FK506 medication was 4.25 ± 3.42 and 4.02 ± 3.83 ng/ml, respectively, for the capsules and the granules. FK506 granules, a new formulation, showed an efficacy comparable to that of the FK506 capsular formulation. Received: 28 July 1997 Received after revision: 25 November 1997 Accepted: 14 January 1998     

Kidney transplant outcomes are related to tacrolimus,mycophenolic acid and prednisolone exposure in the first week

This study analysed associations between tacrolimus, mycophenolic acid (MPA) and prednisolone exposures on day 4 and month 1 post kidney transplant and clinical outcomes. Area under the concentration‐time curve (AUC) for each drug was estimated using validated multiple regression‐derived limited sampling strategies. Multivariate logistic regression was used to associate drug exposure with clinical outcomes. One hundred and twenty subjects were studied. Between‐subject variability in dose‐adjusted exposure to each medication was high. Both day 4 tacrolimus and MPA exposures were independently predictive of delayed graft function (2.6 change in odds for a standard deviation (SD) increase in tacrolimus AUC_0–12, P = 0.02; 0.23 change in odds for a SD increase in MPA AUC_0–12, P = 0.02). Both day 4 MPA and total prednisolone exposures were independently predictive of rejection (0.20 change in odds for a SD increase in MPA AUC_0–12, P = 0.04; 0.40 change in odds for a SD increase in total prednisolone AUC_0–6, P = 0.03). Lowest tertile exposure to all three immunosuppressant medications imposed significantly higher odds of rejection [adjusted odds ratio 34.2 (95% CI 4.1, 284.4), P = 0.001]. This study highlights the importance of achieving early target exposure and suggests a potential role for individualized initial dosing or early therapeutic monitoring of all three immunosuppressive agents.     

The weight of pharmacokinetic parameters for mycophenolic acid in prediction of rejection outcome: the receiver operating characteristic curve analysis

Often the clinical researcher is confronted with the question of how accurate a particular laboratory test is to identify disease. To confirm the ability of pharmacokinetic (PK) parameters to discriminate between patients with or without acute rejection after kidney transplantation, an analysis of receiver operating characteristic (ROC) curves was performed in 51 adult patients, among whom nearly 50% experienced biopsy-proven acute rejection episodes during the first 90 days posttransplant. All patients received cyclosporine or tacrolimus, prednisone, and mycophenolate mofetil (MMF). The following PK variables were determined for mycophenolic acid, an active metabolite of MMF: predose (C₀), maximum concentration (C_max), and area under the concentration-time curve (AUC_0-12h). ROC plots of sensitivity versus 1-specificity were generated to determine whether a particular PK parameter could discriminate renal transplant recipients with an acute rejection from those who experienced no rejection. Area under the ROC curves and the 95% confidence interval limits were calculated using the method of Hanley and McNeil. The C₀ and C_max were less predictive values for acute rejection than AUC_0-12h. The AUC parameter appeared the most effective to discriminate an acute rejection episode during MMF therapy. This study indicated the utility of ROC curve analysis to select PK parameters to predict acute rejection episodes.     

Pharmacokinetics and pharmacodynamics of mycophenolic acid in stable renal transplant recipients treated with low doses of mycophenolate mofetil

Abstract Suboptimal doses of mycophenolate mofetil (MMF) are frequently employed in renal transplant (Tx) patients, with drug‐related side effects or low weight. The aim of this study was to compare the mycophenolic acid (MPA) pharmacokinetic profile and its pharmacodynamic effect on patients receiving either standard (2 g) or low (1.5 g or 1 g) MMF doses, in order to evaluate the therapeutic efficacy of such low doses in inhibiting IMPDH activity. Twenty‐seven stable renal Tx recipients aged 18‐65 years, with a post‐Tx follow‐up of 38.5 ± 44.8 months (6‐166 months), receiving 1 g (n = 10), 0.75 g (n = 7) and 0.5 g (n = 10) MMF twice a day in association with cyclosporine and prednisone, were included. The control group was made up of untreated healthy volunteers (n = 5). Plasma concentrations of MPA were analyzed by reverse‐phase HPLC. IMPDH activity was determined in lymphocytes by the measurement of ³H release from [2,8‐³H] hypoxantine. The mean value of areas under the concentration‐time curves (AUC_0‐12) of MPA throughout the 12‐h dosing interval in patients treated with 2 g was higher than the corresponding data in patients receiving 1.5 g or 1 g bid, but no statistical differences were observed between the three groups. There was no correlation between MPA‐AUC_0‐12 values and MMF dose (expressed in g/day or g/kg per day). Predose MPA concentrations correlated only weakly with the respective MPA‐AUC_0‐12 values (r² from 0.385 to 0.655), whereas an acceptable correlation was observed between MPA C_max and MPA‐AUC_0‐12 (r² from 0.626 to 0.759) in 2 g, 1.5 g, and 1 g MMF groups. An inverse relationship between MPA concentrations and IMPDH activity was observed. In general, the maximum MPA concentration was achieved from 1 h to 2 h after dosing, and the maximum inhibition of IMPDH was also from 1 h to 2 h after dosing. The evaluation of IMPDH activity demonstrated that there was a significant statistical difference between samples from 0 to 1 h (P = 0.008) and 0 to 2 h (P = 0.04). In conclusion, concentration‐time profiles of renal transplant recipients administered 0.75 g and 0.5 g twice a day are slightly lower than those from the 2 g group, but nor significantly. On the other hand, inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability. Pharmacodynamic monitoring of the degree of immunosuppression and its correlation with MPA plasma concentrations will be assessed further in future studies.     

Absorption phase cyclosporine (C<Subscript>2 h</Subscript>) monitoring in the first weeks after pediatric renal transplantation

Cyclosporine (CsA) monitoring using abbreviated area under the curve or 2-h blood concentration (C_{2 h}) has been shown to predict total drug exposure in adult renal transplantation. However, pediatric experience is limited. Since 1998, we have monitored C_{2 h} in 45 children (age 10.6±4.7 years) during the first 6 weeks after transplantation. In 22 a 4-h CsA profile (AUC_0–4h) was available and C_{2 h} in the remaining 23 patients. In addition CsA profiles from 24 children transplanted before 1998 were used to calculate the correlation between single time points and AUC_0–4h. The best correlation between AUC_0–4h and a single time point was seen with C_{2 h} ( r ²=0.89). C_{0 h} did not predict AUC_0–4h reliably ( r ²=0.27). C_{2 h} showed the lowest prediction error (10.0±9.6%). No dependency on age could be detected. In the first 3 months following transplantation, rejection was observed in 9 of 45 patients (20%). Glomerular filtration rate remained stable within the first 5 years after transplantation. In conclusion, in the early phase after renal transplantation, C_2h can be used to predict drug exposure within the whole pediatric age group and should be evaluated in prospective trials.     

Tacrolimus pharmacokinetics in Hispanic children after kidney transplantation

Ethnic differences in drug pharmacokinetics are well recognized including that for tacrolimus (TAC) in adult subjects. However, similar knowledge among pediatric populations is missing. Our limited retrospective study compares steady-state pharmacokinetics of TAC in Hispanic versus non-Hispanic children. Serial blood samples were collected and whole blood concentrations of TAC were measured using radioimmunoassay. Compared with non-Hispanic children, Hispanic children had lower measures of drug exposure (maximum drug concentration [C_max] and area under the drug concentration-time curve [AUC_0-∞]), higher volume of distribution, and faster clearance. Interestingly, only in Hispanic children, significant correlations were found between body weight and clearance, age and volume of distribution, and Schwartz estimated glomerular filtration rate and half-life. In conclusion, our study suggests that ethnic differences exist between Hispanic and non-Hispanic children in TAC PK, and based on our preliminary findings, either a higher or more frequent TAC dosing may be required for effective immunosuppression therapy in Hispanic children.     

Pharmacokinetics of ganciclovir in pediatric renal transplant recipients

Ganciclovir (GCV) is effective in preventing and treating cytomegalovirus (CMV) infection in solid organ transplant recipients. The aims of the present study were to determine the pharmacokinetics of GCV administered intravenously (IV) and orally (p.o.) as pre-emptive anti-CMV therapy in pediatric renal transplant recipients and to monitor trough levels and side-effects during pre-emptive therapy. Eleven pediatric renal transplant recipients (aged 11.0±3.9 years) were included. The diagnosis of CMV infection, based on two positive pp-65 CMV blood antigen tests at 1 week apart, was made at 39±12 days post renal transplantation. They received IV GCV at a dose of 5.0±0.3 mg/kg per 12 h for 15 days, followed by GCV p.o. at a dose of 46.7±8.2 mg/kg per 12 h for 3 months. Pharmacokinetics (PK) were studied at steady state and GCV plasma concentrations were measured by high-performance liquid chromatography. After IV GCV administration, PK parameters were: C₀=0.84±0.66 g/ml; C_max=11.77±2.82 g/ml; AUC_{0–12 h}=42.29±17.57 g/ml per hour; Cl=0.13±0.05 l/h per kg. After p.o. GCV administration, PK parameters were: C₀=1.08±0.68 g/ml; C_max=2.70±1.07 g/ml; AUC_{0–12 h}=18.97±9.36 g/ml per hour; Cl/F=2.97±1.42 l/h per kg. Bioavailability (F) was 4.9±1.2%. Pre-dose concentrations (C₀) measured under p.o. GCV (n=51) were 1.29±0.80 g/ml (8 C₀ values were below 0.5 µg/ml). Pp-65 CMV blood antigen tests became negative after 16±11 days of treatment. GCV was well tolerated. Because of the limited bioavailability, the recommended high doses of p.o. GCV (50 mg/kg per 12 h) were administered and were associated with trough levels over 0.5 µg/ml. In 1 patient who received an erroneously low dosage p.o., CMV resistance to GCV appeared, requiring foscarnet.     

Pharmacokinetics of mycophenolic acid, tacrolimus and sirolimus after gastric bypass surgery in end-stage renal disease and transplant patients: a pilot study

Abstract: Background: Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. Methods: Data are presented on six subjects who participated in this trial – four were on dialysis and two were renal transplant recipients. Dialysis‐dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4‐mg doses of tacrolimus and two 1000‐mg doses of mycophenolate mofetil (MMF) over the 24‐h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (C_max), time to reach the maximum plasma concentration (T_max) and the area under the plasma concentration vs. time curve (AUC_0–12 and AUC_0–∞ where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). Results: Significant inter‐patient variability in the C_max, T_max and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non‐bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. Conclusions: When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non‐bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non‐bypass patient.     

Impact of early cyclosporin average blood concentration on early kidney transplant failure

This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C₀), average concentration values (C_av; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (C_max), and time to maximum concentration (t_max) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial C_av≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with C_av < 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with C_av < 550 versus C_av≥ 550 ng/ml at 30 (88 % vs 96 %; P < 0.02), 60 (85 % vs 94 %; P < 0.007), 90 (85 % vs 94 %; P < 0.02), and 180 (83 % vs 92 %; P < 0.05) days. Moreover, patients with C_av < 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed C_av≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C₀, C_max, and t_max values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of C_av correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival. Received: 27 May 1997 Received after revision: 8 August 1997 Accepted: 21 August 1997     

Limited sampling strategy for the estimation of mycophenolic acid area under the curve in Tunisian renal transplant patients

Mycophenolate mofetil is a prodrug widely used in renal transplantation to prevent organ rejection. It is hydrolyzed to its active compound mycophenolic acid (MPA). MPA area under the curve (AUC_0−12h) is considered the best pharmacokinetic parameter for the estimation of MPA exposition and for prediction of rejection. MPA-AUC requires several blood samples, making it impractical for clinical practice. Therefore, development of a limited sampling strategy (LSS) to estimate MPA AUC_0−12h using three blood samples is very helpful for MPA individual dose adjustment. Results of LSS differ according to the patient background and to the drug formulation. Therefore, the purpose of this study was to develop a LSS for the estimation of MPA AUC_0−12h in Tunisian renal transplant patients treated with the generic formulation of mycophenolate mofetil (MMF^®, MEDIS). The best correlation was achieved by a profile based on three time points C_0.5h, C_1.5h, and C_4h after drug intake: AUC_0−12h = 0.414 + 1.210 × C_0.5 + 2.256 × C_1.5 + 4.134 × C₄ (mei = 1.65% and rmse = 5.81%). The correlation between full AUC_0−12h and abbreviated AUC_0-12h was 0.917. In conclusion, this model provides a reliable and simple equation to estimate MPA AUC_0−12h for the generic formulation of mycophenolate mofetil (MMF^®).     

The relative importance of cyclosporine exposure in heart,kidney or liver transplant recipients on maintenance therapy

We investigated the relationship between cyclosporine exposure and the presence of cyclosporine-related side effects and assessed the advantage of the cyclosporine concentration 2 h post-dose (C₂) over pre-dose concentration (C₀) monitoring. Cyclosporine area-under-the-concentration–time curves were measured during the absorption phase (AUC_{0–4 h}) in 49 liver, 28 heart and 26 kidney transplant recipients (time since transplantation >6 years) with or without cyclosporine-related side effects on maintenance therapy. The cyclosporine C₀ correlated well with AUC_0–4 (r=0.77), whereas C₂ levels correlated strongly with AUC_0–4 (r=0.92). Although we observed a trend towards higher CsA concentrations in transplant recipients with side effects than in patients without CsA toxicity, the large majority of those differences were not statistically significant. Thus, as cyclosporine exposure was not clearly related to the presence of side effects, and C₀ correlated fairly with AUC_0–4, the advantage of monitoring cyclosporine treatment using C₂ rather than C₀, may be limited for patients on cyclosporine maintenance therapy.     

Pharmacokinetics and Mammary Residual Depletion of Erythromycin in Healthy Lactating Ewes

The aim of this investigation was to examine the pharmacokinetics and mammary excretion of erythromycin administered to lactating ewes (n = 6) by the intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) routes at a dosage of 10 mg/kg. Blood and milk samples were collected at pre‐determined times, and a microbiological assay method was used to measure erythromycin concentrations in serum and milk. The concentration–time data were analysed by compartmental and non‐compartmental kinetic methods. The serum concentration–time data of erythromycin were fit to a two‐compartment model after i.v. administration and a one‐compartment model with first‐order absorption after i.m. and s.c. administration. The elimination half‐life (t_1/2β) was 4.502 ± 1.487 h after i.v. administration, 4.874 ± 0.296 h after i.m. administration and 6.536 ± 0.151 h after s.c. administration. The clearance value (Cl_tot) after i.v. dosing was 1.292 ± 0.121 l/h/kg. After i.m. and s.c. administration, observed peak erthyromycin concentrations (C_max) of 0.918 ± 0.092 μg/ml and 0.787 ± 0.010 μg/ml were achieved at 0.75 and 1.0 h (T_max) respectively. The bioavailability obtained after i.m. and s.c. administration was 91.178 ± 10.232% and 104.573 ± 9.028% respectively. Erythromycin penetration from blood to milk was quick for all the routes of administration, and the high AUC_milk/AUC_serum (1.186, 1.057 and 1.108) and C_max‐milk/C_max‐serum ratios reached following i.v., i.m. and s.c. administration, respectively, indicated an extensive penetration of erythromycin into the milk.