High intra-individual variability of cyclosporine pharmacokinetics in lung transplant recipients without cystic fibrosis.

BACKGROUND: There has been little study on the variability of CsA pharmacokinetics in stable lung transplant (LT) recipients without cystic fibrosis. This study was conducted to determine the prevalence of high intra-individual variability of CsA in LT recipients and its implications in CsA monitoring. METHODS: Twenty-nine pharmacokinetic curves were performed in 10 consecutive stable patients from a single center. The intra-individual coefficient of variation (CV) of the AUC0₋12 h was calculated in each case. Patients were grouped according to whether their CV was high (≥20%) or low (<20%). Correlations between cyclosporine CsA concentration at each time point, AUC0₋4 h , and AUC0₋12 h were also calculated. RESULTS: Six (60%) patients presented low CVs and four (40%) high CVs. In patients with low CVs, the best correlation of AUC0₋12 h was with CsA concentration at two h post-dose (C2) (r = 0.674, p = 0.002), whereas in those with high CV, the best correlation was with C5 (r = 0.800, p = 0.003). In the latter group, the correlation with C2 was low (r = 0.327, p = 0.32), whereas the correlation with C0 was high (r = 0.709, p < 0.05). CONCLUSIONS: Intra-individual variability of CsA pharmacokinetics may be high in many LT recipients. In patients with high CV, the use of C0 levels may be more appropriate for CsA monitoring than C2 levels.

Pharmacokinetic study of conversion from tacrolimus twice-daily to tacrolimus once-daily in stable lung transplantation.

BACKGROUND: Tacrolimus twice-daily (TAC BID) is widely used in lung transplantation (LT), but there are little data on the use of tacrolimus once-daily (TAC QD) in this population. The objective of this study was to compare the pharmacokinetics (PK) of TAC BID and TAC QD in stable, adult LT patients. METHODS: Phase II, open-label, single-center, single-arm, prospective pilot PK study. Nineteen LT recipients with more than 6 months of postoperative follow-up and on TAC BID-based therapy were converted to TAC QD on a 1:1 (mg/mg) basis. Patients had been stable during the previous 3 months, and cystic fibrosis patients were excluded. One 24-hr PK profile was obtained on day -14 while patients were under TAC BID. A second PK profile was obtained 14 to 28 days after switching (day 0) to the same dose of TAC QD. Pre- and post-switch 24-hr PK profiles were compared. RESULTS: Mean AUC0-24 hr was 279.8 ng mL/hr for TAC BID and 278.7 ng mL/hr for TAC QD (P=0.92). AUC0-12 hr of TAC BID was higher than the AUC12-24 hr. There was a good correlation between AUC0-24 hr and C24 for both QD (r=0.96) and BID (r=0.94) formulations. There were no differences in the adverse events occurring with the two formulations. CONCLUSIONS: Tacrolimus bioavailability in steady state is similar in BID and QD formulations after conversion in stable LT recipients, excluding those with cystic fibrosis. Thus, our results indicate TAC BID can be safely switched to the more convenient QD formulation in this population.

Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study.

OBJECTIVES: To evaluate voriconazole plasma level monitoring in immunocompromised children and determine the relationship of plasma levels with dose, safety and efficacy. METHODS: We used a prospective study including all consecutive children with invasive fungal infection (IFI) treated with voriconazole between August 2008 and May 2010. IFI diagnosis and clinical outcome evaluation were based on European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group ('EORTC/MSG') definitions. RESULTS: A total of 196 voriconazole plasma trough measurements from 30 patients (median age 10 years) obtained during 2135 days of voriconazole therapy were analysed. Nineteen patients (63%) presented with proven or probable IFI. Voriconazole plasma levels varied widely and 73% of patients required dose adjustment. The median voriconazole dose was 20 mg/kg/day and the median duration of therapy was 6 weeks. Age 5 was the smallest value defining two groups on which the correlation between dose and plasma levels had a different behaviour, and this relationship was especially significant for patients <5 years old (Spearman's rank correlation coefficient=0.38213, P=0.008). For patients <5 years old the median dose to achieve therapeutic levels was 38.0 mg/kg/day (12-40.0) and for those ≥5 years old it was 15 mg/kg (4-52). Voriconazole plasma levels showed a significant relationship with early outcome (P=0.0268), but not late outcome (P=0.2015). Overall mortality was 42% and a significant relationship with voriconazole therapeutic plasma levels was not demonstrated. A significant relationship was established between plasma levels above normal range and skin and neurological toxicity (P=0.0001), but this could not be demonstrated for liver toxicity. CONCLUSIONS: Our study confirms the large variability in voriconazole trough plasma levels in children and a trend to non-linear pharmacokinetics in older patients. In addition, doses significantly higher than those recommended in younger children seem warranted and a significant relationship between plasma voriconazole above the normal range and some adverse events is confirmed.

State of the art in therapeutic drug monitoring.

Therapeutic drug monitoring (TDM) is a multidisciplinary activity. Because laboratory reports are part of the patient's chart, some clinical information is required. In order to guarantee quality and safety, an increasing number of TDM departments have implemented a quality management system. The aim of the present article is to review the three phases of TDM: the pre-analytical, analytical and post-analytical phases. In the pre-analytical phase, it is necessary to acquire a valid specimen collected at the specific time window. Analytical methods should be validated, assessing possible interfering substances. The objective of the post-analytical phase is the final report, which should include correct interpretation, as well as possible advice. Appropriate pharmacokinetic interpretation avoids unnecessary costs and leads to clinical benefits.

Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety.

BACKGROUND: The main problem with using nebulized liposomal amphotericin (n-LAB) as prophylaxis for Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and its possible adverse effects. The aim of this study was to measure post-inhalation amphotericin B concentration in the respiratory tract and serum of lung transplant patients and assess the effects of n-LAB on respiratory function. METHODS: Thirty-two consecutive bronchoscopies were performed on 27 lung transplant patients at two hospitals. Amphotericin B concentration in the first and third aliquot of bronchoalveolar lavage material was measured in steady state. The first aliquot approximates most closely the true amphotericin B concentrations in the proximal airway, whereas the third aliquot provides an optimum sample from the distal airway. RESULTS: At 2 days, mean amphotericin B concentrations were 11.1 microg/ml (95% confidence interval [CI]: 16.5 to 5.7 microg/ml) and 9.0 microg/ml (95% CI: 14.3 to 3.8 microg/ml) in the first and third aliquot, respectively. Thereafter, concentrations declined progressively. At 14 days, concentrations were 3.0 microg/ml (95% CI: 4.4 to 1.5 microg/ml) in the first aliquot and 4.1 microg/ml (95% CI: 6.1 to 2.1 microg/ml) in the third aliquot (p = not statistically significant). Traces of amphotericin B (0.1 microg/ml) were found in serum samples from only 1 of 27 patients. Mean value of forced expiratory volume in the first second (FEV(1)) was similar before and after n-LAB. CONCLUSIONS: Amphotericin B concentrations after n-LAB remained high for 14 days, at adequate concentrations for prophylaxis of Aspergillus infection. No significant systemic absorption of amphotericin B was detected and no effect was observed on respiratory function. This promising prophylactic regimen warrants assessment in future clinical studies.

Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.

OBJECTIVES: To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs). METHODS: Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. RESULTS: Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. CONCLUSIONS: There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

Early monitoring of ribavirin serum concentration is not useful to optimize hepatitis C virus treatment in HIV-coinfected patients.

BACKGROUND: Emerging data suggest that higher ribavirin (RBV) exposure could improve early hepatitis C virus (HCV) response. Furthermore, interindividual RBV bioavailability shows high variation, and dose-limiting haemolytic anaemia is a common adverse event. Therefore, it has been suggested that monitoring RBV serum levels could be used to drive dose modification and to optimize management of HCV-infected patients receiving combination treatment. METHODS: To assess the effect of RBV serum levels on HCV RNA clearance at week 4 and 12 of treatment, and to determine the correlation between RBV serum concentration and haemoglobin decrease, RBV trough levels were measured by HPLC in stored serum samples obtained from 94 HCV-HIV-coinfected patients at week 4 and 12 of treatment with peginterferon-alpha2b (1.5 microg/kg/weekly) pIus ribavirin (800-1,200 mg/day). RESULTS: The median RBV levels increased from 1.70 microg/ml at week 4 to 1.97 microg/ml at week 12 of treatment (P = 0.001) and were independently predicted by weight-adjusted dose of RBV and co-administration of tenofovir. Haemoglobin drop was higher among patients who received zidovudine and weakly correlated with RBV level. Although RBV concentration was lower in genotype 1 or 4 HCV-infected patients who cleared the virus at treatment week 4, the ability of this parameter to discriminate between responders and non-responders at treatment week 4 and 12 was poor. CONCLUSION: Intracellular RBV accumulation early in treatment might improve the kinetics of HCV response in difficult to treat patients. Although this hypothesis and the potential interaction between RBV and tenofovir warrant further research, our data do not support RBV serum monitoring as a tool to optimize treatment in HCV-HIV-coinfected patients.

Immunosuppression based on mycophenolate mofetil in stable liver transplanted patients.

AIM: To analyze our results with mycophenolate mofetil (MMF) in stable liver transplantation (LT) patients presenting with adverse events (AE) related to prolonged use of calcineurin inhibitors (CNI). METHODS: Conversion to MMF was performed in 56 out of 323 LT patients from 91-02: 24 (43%) were converted to MMF in monotherapy and 32 (57%) to MMF+low doses of CNI. The indication for conversion was chronic renal insufficiency (CRI) in all patients. The mean time between AE and conversion was 38.7+/-30 months (r: 2-101 m). Post-conversion follow-up was 39+/-20 months (r: 3-72 m). RESULTS: The calculated creatinine clearance (Crauckoft), improved significantly in all patients. In those converted to MMF, improvement was seen during the first 18 months for urea and during the first 6 months for creatinine. In patients converted to MMF+CNI, improvement was maintained throughout the conversion period for both urea and creatinine. Eleven (19.6%) patients underwent acute rejection (2 severe episodes in the MMF group and 1 death). Hypertension was present in 31 patients but only improved in 4 (7%). Dyslipemia was found in 12 and improved in 4 (7%). DM was present in 14 and improved in 1 (2%). CONCLUSIONS: Conversion to MMF in monotherapy is useful in stable LT patients with CRI due to CNI, although this result is offset by more severe rejections. Therefore, for AE secondary to CNI, we propose an early conversion to MMF+low doses of CNI as a first step. If liver function remains stable and AEs persist or progress, conversion to MMF in monotherapy is recommended, as a second step, with close monitoring of the patient.

Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen.

OBJECTIVE: To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) and atazanavir (ATV) as a double-boosted protease inhibitor regimen in HIV-infected adults. METHODS: Sixteen patients who started LPV/RTV (400/100 mg b.i.d.) and ATV (300 mg q.d.) were enrolled in the study group (arm A). LPV pharmacokinetics were compared to those of two historical groups: arm B, 15 patients who received LPV/RTV (400/100 mg b.i.d.); and arm C, 25 patients who received LPV/RTV/saquinavir (SQV) (400/100/1000 mg b.i.d.). ATV pharmacokinetics were compared to those of 15 consecutive patients who received ATV and RTV (300/100 mg q.d.) (arm D). Drug concentrations were measured by HPLC. RESULTS: LPV concentrations were significantly higher in arm A than in arms B and C. Median (interquartile range) LPV area under the curve (AUC)0-12 values were 115.7 (99.8-136.5), 85.2 (68.3-109.2) and 85.1 (60.6-110.1) microg/h/ml, respectively. C(max) values were 12.2 (10.7-14.5), 9.5 (6.8-13.9) and 10.0 (6.9-13.6) microg/ml, respectively. C(min) values were 9.1 (7.1-10.4), 5.6 (4.7-8.2) and 5.5 (4.2-7.5) microg/ml, respectively. No difference was observed for ATV AUC0-24 or C(max) between arms A and D. ATV C(min) values were 1.07 (0.61-1.79) in arm A and 0.58 (0.32-0.83) in arm D (P = 0.001). Treatment was not discontinued in any patient because of adverse effects. At 24 weeks, viral load was < 50 copies/ml in 13 of 16 patients. CONCLUSIONS: The combination of ATV and LPV/RTV provided high plasma concentrations of both PI, which seemed to be appropriate for patients with multiple prior therapeutic failures, yielding good tolerability and substantial antiviral efficacy.

A prospective randomized trial comparing tacrolimus and steroids with tacrolimus monotherapy in liver transplantation: the impact on recurrence of hepatitis C.

The aim of this prospective randomized trial was to study the efficacy and safety of tacrolimus monotherapy (TACRO) and compare it with our standard treatment of tacrolimus plus steroids (TACRO + ST) after liver transplant (LT). Furthermore, the impact of steroid-free immunosuppression on outcome of hepatitis C virus (HCV) was analysed. Between 1998 and 2000, 60 patients (mean age: 57 years) were included in the study and randomized to receive TACRO (n = 28) or TACRO + ST (n = 32). Indication for LT was postnecrotic cirrhosis in all cases (58.3% were HCV-positive). Mean follow-up was 44 months. Survival, incidence of rejection, infection and side-effects were compared between the two groups. In patients with HCV infection, incidence and severity of acute hepatitis C, long-term outcome of recurrent hepatitis C and survival were studied in an intention-to-treat analysis or in the real group analysis (real-TACRO versus real-TACRO + ST). Patient survival at 1, 3 and 5 years, tacrolimus pharmacokinetics, incidence of rejection infections and side-effects were similar. In patients with HCV, the incidence and severity of graft hepatitis C tended to be lower in TACRO (47%) compared with TACRO + ST (67%) (P = NS), and also in real-TACRO (42%) compared with real-TACRO + ST (61%) (P = NS). A poor outcome considered as evolution to cirrhosis at 3 years was observed in one (9%) living patient in real-TACRO and nine (45%) in real-TACRO + ST (P = 0.04). Patient survival at 1, 3 and 5 years was 92%, 92% and 73% for real-TACRO and 78%, 61% and 51% for real TACRO + ST (P = 0.07). Steroid-free immunosuppression appears to be safe and efficacious. The main advantage of this regimen could be in HCV patients, as recurrence of hepatitis in the graft was less severe in the group of patients in whom steroids could be avoided completely.

Hematocrit influences immunoassay performance for the measurement of tacrolimus in whole blood.

The comparison between the MEIA II and the EMIT assays for tacrolimus measurement and the interference by the hematocrit were evaluated in 93 samples from routine therapeutic monitoring at tacrolimus concentrations less than 9 microg/L (group A). Additionally, the incidence of false-positive results were determined in samples (n=46) from patients who were not receiving the drug (group B). In group A, no statistical differences were observed between the mean+/-SD values obtained by MEIA II (5.14+/-2.28 microg/L) and EMIT (4.61+/-1.79 microg/L). The correlation coefficient and the regression equation (95% CI) between both assays, were 0.761 and EMIT=1.088 (0.90, 1.35) MEIA II -0.38 (-1.65, -0.46), respectively. When the samples were stratified according to the hematocrit, the median differences between the methods (MEIA II minus EMIT) were as follows: hematocrit35%, 0.25 microg/L (P=0.02). In group B, false-positive results (above the detection limit) were observed in 63.04% of samples analyzed by MEIA II and in 2.17% of samples analyzed by EMIT. The median differences in apparent tacrolimus results were significantly higher in the samples with the lowest hematocrit: 2.2 microg/L, 1.4 microg/L, and 0.0 microg/L in samples with hematocrit35%, respectively. In conclusion, the differences in the tacrolimus results obtained by MEIA and EMIT assays were higher in samples from patients with hematocrit less than 25%, and the MEIA assay demonstrated a high incidence of false-positive results.

Once-daily regimen of saquinavir, ritonavir, didanosine, and lamivudine in HIV-infected patients with standard tuberculosis therapy (TBQD Study).

OBJECTIVES: To assess the efficacy and safety of a once-daily regimen with didanosine, lamivudine, saquinavir, and low-dose ritonavir in antiretroviral (ARV)-naive patients with tuberculosis treated with rifampin and the influence of rifampin on plasma trough concentration (Ctrough) of saquinavir. METHODS: Single-arm, prospective, multicenter, open-label pilot study, including 32 adult ARV-naive subjects with HIV infection and tuberculosis under standard treatment that included rifampin (600 mg q.d.) and isoniazid (300 mg q.d.). After 2 months of tuberculosis treatment, patients were started on once-daily ARV therapy, consisting of didanosine, lamivudine, ritonavir (200 mg), and saquinavir soft gel capsules (1600 mg). HIV RNA level, CD4 cell count, clinical and laboratory toxicity, and saquinavir Ctrough during and after antituberculosis therapy were analyzed. RESULTS: After 48 weeks of follow-up, 20 of 32 patients (62.5%; 95% CI: 45.8% to 79.2%) in the intent-to-treat population and 20 of 28 (71.4%; 95% CI: 54.4% to 88.4%) in the on-treatment population had an HIV RNA level <50 copies/mL. Treatment tolerance was acceptable in all patients except for 2 with biologic hepatic toxicity leading to discontinuation. Seven patients had virologic failure. In 10 patients (36%), saquinavir Ctrough was <0.05 microg/mL during tuberculosis therapy and 5 of them had virologic failure. The median saquinavir Ctrough was 44% lower (interquartile range: 19% to 71%) with coadministration of rifampin than without. CONCLUSION: The combination of didanosine, lamivudine, saquinavir, and ritonavir may be a useful treatment regimen for patients with tuberculosis in whom a once-daily protease inhibitor-containing regimen is considered indicated. Nevertheless, on the basis of pharmacokinetic profile the dose of 1600/200 mg of saquinavir/ritonavir cannot be recommended. Further studies with higher doses of saquinavir (2000 mg) boosted with ritonavir are warranted.

Evaluation of a limited sampling strategy to estimate area under the curve of tacrolimus in adult renal transplant patients.

Limited sampling strategies have been developed to predict full AUCs. The goal of this study was to develop a limited sampling strategy to estimate the AUC of tacrolimus in adult renal transplant patients and to evaluate its predictive performance in an independent patient population. A total of 27 tacrolimus pharmacokinetic profiles were studied. Blood samples were collected before the dose (0) and at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. The study was divided into 2 phases. In phase 1, the goal was to obtain a sampling strategy from 14 pharmacokinetic profiles. In phase 2, the bias and precision of the model were evaluated in another 13 pharmacokinetic profiles. The best correlation was achieved at 4 hours after dose (r(2) = 0.790). Stepwise multiple regression analysis determined that the abbreviated AUC at 0, 1, and 4 hours could accurately predict total AUC (r(2) = 0.965). The following formula was developed: AUC = 8.90 + 4.0C0h+ 1.77C1h + 5.47C4h. No significant differences were found between calculated and estimated AUC (165.6 +/- 41.1 and 166.7 +/- 43.2 ng.h/mL, respectively). The mean prediction error (MPE), the relative prediction error (PE), and the mean squared error (MSE) were 0.48 ng.h/mL, 0.16%, and 40.0 ng.h/mL, respectively. The limited sampling with use of the 3 levels at 0, 1, and 4 hours postdose provides accurate, reliable determination of tacrolimus AUC in renal transplant patients.

Steady-state pharmacokinetics of a double-boosting regimen of saquinavir soft gel plus lopinavir plus minidose ritonavir in human immunodeficiency virus-infected adults.

Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients.

BACKGROUND: A criticism of using nebulized amphotericin B (nAB) as prophylaxis against Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and distribution in the lung. The aim of this study was to ascertain the concentrations and distribution of nAB in the respiratory tract of patients receiving lung transplantations. METHODS: In the drug-concentration study, 120 bronchoscopies were performed in 39 patients receiving lung transplantions after administration of 6 mg of nAB once daily for a minimum of 7 days. Mean nAB concentration in bronchial aspirated secretions (BAS) and bronchoalveolar lavage (BAL) was determined at 4, 12, 24, and 48 hours postnebulization. In the distribution study, 17 patients inhaled 6 mg of 99m technetium-labeled AB, and pulmonary distribution was measured using a gamma camera. Pulmonary perfusion was also measured. Both tests were quantitatively evaluated. RESULTS: In the drug-concentration study, mean concentrations of 1.46 microg/mL in BAS and 15.75 microg/mL in BAL were reached at 4 hours. At 24 hours, concentrations were 0.37 microg/m and 11.02 microg/mL in BAS and BAL, respectively. In the distribution study, 99m technetium-labeled AB distribution was uniform in 12 of 13 allografts without bronchiolitis obliterans syndrome (BOS) and in 1 of 4 allografts with BOS. A close correlation was observed between regional drug distribution and regional perfusion (r=0.82, P<0.01). CONCLUSIONS: nAB concentrations remained high for the first 24 hours in BAL and for less time in BAS, with distribution of the drug being uniform in patients without BOS. Furthermore, lung-perfusion studies appear to be useful to ascertain nAB distribution in patients receiving lung transplantions.

Combined therapy of tacrolimus and corticosteroids in cyclosporin-resistant or -dependent idiopathic focal glomerulosclerosis: a preliminary uncontrolled study with prospective follow-up.

BACKGROUND: Cyclosporin has improved the outcome for steroid-resistant patients with focal glomerulosclerosis, but there is a proportion of patients that are either cyclosporin-resistant or suffer relapses, needing long-term therapy to sustain the remission. In these cases, preliminary reports suggest that tacrolimus could be an alternative therapy, but to date the evidence is limited to small series of patients with no long-term follow-up. METHODS: In this study we analysed the efficacy and safety of a combined therapy of tacrolimus and steroids in 25 patients (mean serum creatinine= 1.24+/-0.49 mg/dl; mean proteinuria=10.2+/-9.5 g/day; mean serum albumin=2.4+/-0.58 g/dl) with idiopathic primary focal glomerulosclerosis and proven resistance to or dependence on cyclosporin A. RESULTS: After a 6 months trial of tacrolimus and steroids, proteinuria decreased in 17 patients (68%) (complete remission in 10 patients (40%), partial remission in two patients (8%) and a moderate reduction in proteinuria to levels <3 g/day was seen in five additional patients (20%)). The only predictor of response to tacrolimus was a previous response to cyclosporin and prednisone, either as a complete or partial remission (remission rate 75% vs 15.3; P=0.036). Mean time to remission was 112+/-24 days. After tacrolimus discontinuation, 13/17 patients (76%) relapsed and were treated with a second trial of tacrolimus for 1 year, achieving complete remission in five patients (38.4%), partial remission in four patients (30.7%) and reduction of proteinuria <3 g/day in four patients (30.7%). After 2 years of follow-up, 12 patients (48%) were on sustained remission. The main side effect was acute reversible nephrotoxicity (40%). Predictors of renal toxicity were age (P=0.037), baseline creatinine (P=0.046) and tacrolimus trough level (P=0.001). CONCLUSIONS: We conclude that combined therapy of tacrolimus and steroids induce sustained remission of proteinuria in a significant number of patients with idiopathic focal glomerulosclerosis whose disease was not controlled by the standard therapy of steroids and cyclosporin A.