Pharmacokinetics of cyclosporin: a microemulsion in children with idiopathic nephrotic syndrome

OBJECTIVE: We present a prospective study of a microemulsion of cyclosporin to treat idiopathic nephrotic syndrome in ten children with normal renal function who presented cyclosporin trough levels between 50 and 150 ng/ml and achieved complete remission with cyclosporin. To compare the pharmacokinetic parameters of cyclosporin in idiopathic nephrotic syndrome during remission and relapse of the nephrotic state. METHOD: The pharmacokinetic profile of cyclosporin was evaluated with the 12-hour area under the timeconcentration curve (auc0-12) using seven time-point samples. This procedure was performed on each patient during remission and relapse with the same cyclosporin dose in mg/kg/day. The 12-hour area under the timeconcentration curve was calculated using the trapezoidal rule. All of the pharmacokinetic parameters and the resumed 4-hour area under the time-concentration curve were correlated with the 12-hour area under the timeconcentration curve. ClinicalTrials.gov:NCT01616446. RESULTS: There were no significant differences in any parameters of the pharmacokinetic of cyclosporin during remission and relapse, even when the data were normalized by dose. The best correlation with the 12-hour area under the time-concentration curve was the 4-hour area under the time-concentration curve on remission and relapse of the disease, followed by the 2-hour level after cyclosporin (c2) dosing in both disease states. CONCLUSIONS: These data indicate that the same parameters used for cyclosporin therapeutic monitoring estimated during the nephrotic state can also be used during remission. Larger controlled studies are needed to confirm these findings.

Low-dose cyclosporine treatment for sight-threatening uveitis: Efficacy, toxicity, and tolerance.

Aim: To ascertain the effectiveness, tolerability, and safety of low-dose cyclosporine in the management of sight-threatening uveitis. Materials and Methods: This was a retrospective clinical case series of patients using oral low-dose cyclosporine for the management of sight-threatening uveitis in the uvea clinic (UC). Patients receiving cyclosporine were identified from the clinic database. Main outcome measures were degree of intraocular inflammation, visual acuity and dose reduction of oral steroid for effectiveness and adverse symptoms, systemic hypertension, and raised serum creatinine for tolerability and safety. Results: Intraocular inflammation was improved or stable in 97% of patients, visual acuity was improved or stable in 91%, and oral steroid dosage was reduced in 73% (by half or more in 51%). Adverse symptoms were almost universal, the commonest being peripheral paresthesia/burning in 70% and fatigue in 67%. Significant systemic hypertension developed in 27% and raised creatinine in 30%, necessitating dose reduction. Cyclosporine was discontinued in 35%, being intolerable in 20% and ineffective in 15%. Conclusions: Cyclosporine was found to be effective in reducing inflammation and protecting vision in sight-threatening uveitis. It was safe with proper monitoring, including in children. It had a significant toxicity profile and a high incidence of adverse symptoms which required close supervision, and a prompt dose reduction or drug exchange.

Co-interferências da farmacocinética dos inibidores de calcineurina em associação com micofenolato mofetil em pacientes transplantados renais / Interference of calcineurin inhibitors on the pharmakocinetics of mycophenolic acid in renal transplantation

O ácido micofenólico (MPA) é o metabólito ativo do micofenolato mofetil (MMF), um imunossupressor seletivo para linfócitos amplamente utilizado em transplantes. A exposição ao MPA na fase inicial pós-transplante renal está associada com menor incidência de rejeição aguda e com maior sobrevida do enxerto / Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), a selective lymphocyte anti-proliferative drug. It has been demonstrated that early adequate exposure to MPA is associated with less acute rejection and better long-term outcome in kidney transplantation. To the present, the recommended therapeutic range for MPA is an area under the concentration-time curve...

[ relationship between the plasma level of cyclosporine-A and drug dose in patients of Kermanshah Kidney Transplantation Center]

Nowadays the main problem in transplantation is the complexity of host immune system protection against the immunological and destructive reactions of the transplanted organ. High serum level of the immunosuppressive drug may cause toxicity and low serum level leads to the rejection of the transplanted organ. Cyclosporine has been known as the most effective immunosuppressive drug. Our goal in this study was to determine the relationship between cyclosporine serum level and administered dose in renal transplant recipients in order to find the optimum cyclosporine dose in Kermanshah kidney transplantation center. This descriptive-analytical study with simple sampling was done on 80 renal transplant recipients [51 males and 29 females] in Kermanshah transplantation center. At least 6 months after transplantation, in patients with stable conditions, cyclosporine peak and trough levels were measured by specific monoclonal, Radio Immuno Assay [RIA] method over a period of 3 months. Other biochemical parameters were measured too. Data were analyzed by 2 and ANOVA tests. Mean cyclosporine Trough and Peak levels were 271.9 +/- 85.2 and 904.5 +/- 414.2 ng/ml respectively, for the treatment dose of 3.25 +/- 1.46 mg/kg B.W. There was no significant difference between trough and peak levels in all three administered doses and the range of administered dose was 1.79-4.71 mg/kg B.W. According to the findings, cyclosporine serum concentrations and the administered dose range differed from other studies. This may be due to pharmacologic and pharmacokinetic differences of the drug and individual physiological characteristics of patients. The minimum dose of 1.79 and maximum dose of 4.71 led to optimum treatment in stable patients and could prevent rejection or toxic effects. Cyclosporine peak level was obviously different from other studies; however it showed better relationship with clinical status. Conversion from the routine cyclosporine C[trough] monitoring to C[peak] monitoring is recommended in Kermanshah kidney transplantation center

Ciclosporina A e tacrolimus: uma revisão / Cyclosporine A and tacrolimus: a review

INTRODUÇAO: Monitorização terapêutica de imunossupressores ciclosporina A (CsA) e tacrolimus (FK506) é indispensável para manter níveis estáveis das drogas, evitando para o transplantado a perda do enxerto, no caso de baixas doses, ou a toxicidade, em altas doses, permitindo ajustes individuais. HISTORICO: Na década de 80, foi introduzida a utilização dos potentes imunossupressores CsA e FK506, revolucionando o transplante de órgãos com a diminuição da rejeição. MECANISMO DE AÇAO: A CsA e o FK506 são inibidores da transcrição do primeiro sinal para ativação dos linfócitos T, apresentando estruturas químicas diferentes, mas mecanismos semelhantes. TOXICIDADE: Os principais efeitos relacionados à dose da CsA e do FK506 são a nefro e a neurotoxicidade. Estudos apontam o FK506 como droga alternativa à utilização da CsA porque aquele demonstrou menor nefrotoxicidade e uma reversibilidade dos efeitos neurotóxicos diante da redução da dose. METODOLOGIA ANALíTICA: Na monitorização de rotina para a CsA, os imunoensaios, radioimunoensaio (RIA) e imunoensaio monoclonal com fluorescência polarizada (FPIAm) ocuparam o lugar da cromatografia líquida de alta eficiência (CLAE), detecção ultravioleta (UV). O método de referência para o FK506 é a CLAE com detecção por espectrometria de massa (LC/MS). Porém, metodologias como ensaio imunoenzimático de micropartículas (MEIA) ou enzyme linked imunosorbent assay (ELISA) têm sido utilizadas na rotina laboratorial. CONCLUSAO: Parece existir uma tendência para a substituição terapêutica da CsA pelo FK506 no tratamento imunossupressor, porém ainda não se estabeleceu consenso nessa conduta. A metodologia analítica para a análise da CsA encontra-se bem estabelecida; para o FK506, estudos ainda são necessários.

Análise do nível sanguíneo ideal de ciclosporina no pós-transplante renal precoce / Identifying cycloporin optimal blood levels in early renal transplantation

Receptores de transplante renal foram randomizados, 25 para área sob curva de ciclosporina (AUC0-12) alta e 33, para baixa. Os grupos foram comparáveis. Não houve diferença quanto a incidência de rejeição celular aguda (RCA). Comparando pacientes com e sem RCA através de regressão logística / Kidney transplant patients were randomized into two groups, 25 in the abbreviated 4-hour area under the curve (AUC0-4) high arm and 33 in the low arm. There was no difference in biopsy-proven acute cellular rejection rates...

Current therapeutic indications for ciclosporin

Ciclosporine was launched in therapeutic use in 1978. It marked the transplantation era due to the success of organ transplantation. Ciclosporine is actually used in bone marrow transplantation and in the transplantation of solid organs such as kidney, liver, heart, lungs, lung-heart, pancreas and bowel. It was proven also efficient in the treatment of auto-immune diseases especially in the treatment of psoriasis and nephrotic syndrome. Pharmacokinetic and drug interactions of ciclosporine have to be taken in consideration in order to allow an optimal use of the medication. However, the drug presents a long list of side effects: hypertension, increased level of serum creatinine, hypomagnesemia, severe gingivitis, maxillary modification, which can restrict the therapeutic use of the drug

Laboratory monitoring of cyclosporine per - dose concertration after kidney transplantation in isfahan

Cyclosporine is the main immunosuppressive agent used in organ transplantation which leads to considerable improvement in graft survival. The large inter- and intra- patient variability in cyclosporine pharmacokinetics coupled with the agent's narrow therapeutic index and adverse effects necessitate therapeutic monitoring of cyclosporine blood levels. The aim of this study was to determine the extent of variability following oral administration of cyclosporine after kidney transplantation, and provide guidelines for administration of cyclosporine in Isfahan/Iran The results of 2163 cyclosporine pre-dose blood samples obtained from 647 kidney transplant recipients [208 females, 439 males] with a median age of 34 years [range 11-54 years] were studied. Concentration of cyclosporine in the whole blood was determined by a radioimmunoassay using monoclonal antibodies specific for the drug. Statistical analyses were performed using SPSS. The frequency distribution of C0 and daily oral dosage of cyclosporine exhibited wide interindividual variability. Cyclosporine oral dosage regimen ranged from 100 mg to 400 mg. Trough cyclosporine blood concentration [C0] ranged from 18 micro g/l to 1400 micro g/l. The results of cyclosporine whole blood levels in 56% were always below the suggested therapeutic range [less than 200 micro g/l] and in 14% of the samples seemed to be associated with the occurrence of toxic side effects. There were no significant differences in the median trough levels of kidney recipients according to gender [p = 0.36]. For long-term management of kidney transplant recipients and in order to further optimize the use of cyclosporine, it is essential to standardize laboratory monitoring and clinical investigation of this agent

Comparative bioavailability evaluation of two cyclosporine oral formulations in healthy mexican volunteers

Background. The use of conventional cyclosporine (Sandimmune) requires great care, as this drug exhibits a narrow therapeutic index and wide interindividual variability in its Pharmacokinetics. Recently, a new microemulsion formulation (Neoral) was developed. With this formulation, cyclosporine is absorbed at the small intestine without the presence of bile. Therefore. The objective of this study was to compare the bioavailability of cyclosporine after the administration of conventional and microemulsion formulations in healthy Mexican volunteers in order to approach the optimal dosage regimen of microemulsion in the Mexican population. Methods. The trial was conducted using 23 healthy volunteers according to a randomized crossover design. Volunteers received on 7.5-mg/kg dose as each formulation, with a 1-week washout period between treatment. Blood samples of 0.5 mL were obtained according to the following schedule. 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, and 24 h after medication. Results. These indicated that Cmax and AUC0-24 values were higher with the microemulsion than with the conventional formulation. Conclusions. The microemulsion had a better absorption profile than the conventional formulation, because plasma levels with the conventional formulation demostrated oscilations rather than reflecting an erratic absorption. Lower doses of the microemulsion are required to obtain Cmax values similar tho those obtained with conventional cyclosporine

A review of absorption characteristics of microemulsion cyclosporine products over the last 2 years in Indian subjects.

Microemulsion based cyclosporine has demonstrated better absorption with laser pharmacokinetic variability. For the clinical use of any new microemulsion based product, bioequivalence testing with existing formulation is necessary. Panimun Bioral (Test) and Sandimmun Neoral (Reference) were evaluated in different transplant centers using both volunteers as well as renal transplant patients. All these centres have reported that both products are bioequivalent. These reports offer the physician an option to convert the patients to the Test product for economic reasons.

Conversión de sandimmune a neoral en pacientes trasplantados renales que reciben ciclosporina-ketoconazol / Conversion of sandimmune to neoral in patients with renal transplantation treated with cyclosporine-ketoconazol

Patients and methods: Thirty four patients with more than one year after the transplantation, with stable renal function and receiving triple immunosuppression were studied. Conventional cyclosporine was changed to the microemulsion form maintaining the same daily dose. Drug serum levels, serum creatinine and blood pressure were measured within two to eight months after the conversion. Doses of microemulsion cyclosporine were adjusted to achieve serum levels of 150 ñ 40 ng/ml. Results: Microemulsion cyclosporine induced a slight initial increase in blood cyclosporine levels. Afterwards, levels were more stable than with conventional cyclosporine (165-185 and 145-210 ng/ml respectively) and the dispersion of values were lower (standard deviations of 70 and 100 ng/ml respectively). Twenty three patients did not require dose adjustments, in four it was reduced and in five it was increased. There were no changes in serum creatinine or blood pressure after the conversion. Conslusion: More stable serum levels without adverse reactions were obtained with microemulsion cyclosporine. Doses of cyclos porine need not to be changed during the conversion

Curva AUC farmacocinética reducida y concentraciones promedio de ciclosporina neoral / Curve AUC reduced pharmacokinetics and midle concentrations of neoral cyclosporine

Con los cambios en la formulación así como en los avances en la monitorización hoy es discutible si basta con los niveles basases o es necesario obtener alguna medición más exacta de la exposición del paciente a la ciclosporina. El objetivo de este trabajo es describir la experiencia inicial de monitorización de ciclosporina en el período post trasplante inmediato y comparar la monitorización con nivel basal vs el Arca bajo la Curva (AUC) tanto total como reducido. Aquellos enfermos que no alcanzaron niveles de 300 ng/ml durante la primera semana fueron malos absorbedores y necesitaron una dosis mayor que los que respondieron precozmente. El nivel basal fue un mal indicador de la exposición del enfermo a la ciclosporina, ya que al comparar ambas determinaciones se obtiene una relación de 0.284 (NS). Al correlacionar el AUC promedio con el AUC reducido se observa una correlación de 0.917 (p

Neoral de novo: experiencia preliminar en transplante renal / Novo neoral: preliminary experience in renal transplantation

Se realizó un estudio retrospectivo comparativo entre 2 grupos de enfermos sometidos a un transplante renal en el Hospital Clínico de la Universidad Católica. El estudio incluye la serie de los últimos 12 enfermos que recibieron terapia inmunosupresora con Ciclosporina nueva formulación (Neoral R) y un grupo de control constituido por 11 enfermos con Sandimmun, comparables en histocompatibilidad, isquemia y características generales. El objetivo es estudiar el tiempo que demoran ambas formulaciones de Ciclosporina en alcanzar el rango terapéutico óptimo, la dosis necesaria para alcanzar estos niveles, la repercusión en relación a la función renal y la frecuencia de rechazo. En ambos grupos no hubo diferencias significativas en la fecha de inicio de la Ciclosporina, sin embargo el rango terapéutico óptimo en el grupo que usó Neoral, se alcanzó el día 14 y en el grupo con Sandimmun éste se logró en el día 25 (p = 0,025). La dosis necesaria para alcanzar este rango terapéutico fue similar en ambos grupos (6,2 y 6,8 mg/Kg) (NS). El haber alcanzado una dosis terapéutica en forma más rápida, no afectó la función renal, ya que ambos grupos tuvieron curvas de creatinina similares. La frecuencia de rechazo fue mayor en el grupo tratado con Sandimmun (45 por ciento), en relación a un 9 por ciento del grupo de Neoral (p = 0.042)

Farmacocinética da ciclosporina e de seus metabólicos em pacientes submetidos a transplante renal / Pharmacokinetics of cyclosporine and its metabolites in patients undergoing kidney transplantation

A farmacocinética da ciclosporina demosntra grande variaçäo inter e intra-individual e profundas mudanças säo, freqüentemente, observadas após o transplante renal. OBJETIVO. analisar seriadamente a farmacocinética da ciclosporina e de seus metabólitos através da determinaçäo de sua concentraçäo sanguínea, em pacientes submetidos a transplante renal. MÉTODOS. Foram realizados 70 estudos em 29 pacientes, sendo 26 antes e 44 após o transplante renal. Em cada estudo a curva de absorçäo foi analisada mediante a determinaçäo da concentraçäo sanguínea da ciclosporina, utilizando radioimunoensaio com anticorpos monoclonais específicos (RIE-MoSP) e inespecíficos (RIE-MoNP), em 17 amostras colhidas após a sua administraçäo oral ou endovenosa (0; 0,5; 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 12; 16; 20; 23; 24h). Resultados. A área sob a curva da concentraçäo sanguínea de ciclosporina em funçäo do tempo (AUC), a biodisponibilidade (F), a concentraçäo máxima (Cmax) e as concentraçöes sanguíneas obtidas 12 e 24 horas após a sua administraçäo (C12 e C24), determinadas com RIE-MoSP, foram inferiores àquelas encontradas com RIE-MoNP, enquanto a depuraçäo (CL) e o volume de distribuiçäo (Vd) foram maiores. A meia-vida de eliminaçäo foi semelhante utilizando os dois métodos (t1/2). A absorçäo seguiu uma cinética de ordem zero, sendo observada uma correlaçäo inversa entre a dose de ciclosporina e a AUC/dose (r = 0,55, RIE-MoSP e r = 0,42, RIE-MoNP). A fraçäo de absorçäo (F) variou entre 18 por cento e 68 por cento (RIE-MoSP), sendo superestimada quando determinada com RIE-MoNP (38 por cento a 100 por cento), conseqüência da extensa metabolizaçäo na primeira passagem pelo intestino e fígado...