FK506 (tacrolimus) is a safe and effective immunosuppressant for the prevention of organ rejection after organ transplantation. FK506 has a relatively narrow therapeutic index and the correlation of dose to blood concentration is poor as a result of moderate variability in pharmacokinetic parameters between patients. Therapeutic monitoring of whole blood FK506 drug concentrations has been used in an effort to determine whether a relationship exists between concentrations of FK506 in the blood and the development of toxicity or the risk for organ rejection. An analysis of the relationship between FK506 blood levels and the occurrence of toxicity and rejection was carried out using data from four recent clinical trials. Trough FK506 levels within a 7-day window before the onset of rejection or toxicity were analyzed using logistic regression models. In kidney transplant patients (n=92), a significant correlation between FK506 levels and the incidence of both toxicity (P=0.01) and rejection (P=0.02) was seen. In liver transplant patients from three clinical trials, FK506 levels correlated well with the incidence of toxicity (P < or = 0.01); however, there was no significant relationship between FK506 levels and the incidence of rejection. It is concluded that therapeutic monitoring of whole blood FK506 levels may be useful for minimizing the risks of both toxicity and rejection in kidney transplant patients and for minimizing the risk of toxicity in liver transplant recipients.
This paper compares a variety of two treatment crossover designs under a uniform notation and covariance structure with respect to their ability to provide efficient estimators of contrasts among direct treatment effects when residual effects might be present. The designs are also compared on the basis of their ability to provide additional information on the nature of treatment effects such as estimating second order residual effects and direct by period and direct by first order residual effect interaction. Many of these designs are uniformly more efficient, with respect to estimating direct treatment effects, than either the conventional two period design or the completely randomized design with repeated measurements. Two efficient and effective four sequence designs are discussed in some detail.
This paper compares a variety of two treatment crossover designs under a uniform notation and covariance structure with respect to their ability to provide efficient estimators of contrasts among direct treatment effects when residual effects might be present. The designs are also compared on the basis of their ability to provide additional information on the nature of treatment effects such as estimating second order residual effects and direct by period and direct by first order residual effect interaction. Many of these designs are uniformly more efficient, with respect to estimating direct treatment effects, than either the conventional two period design or the completely randomized design with repeated measurements. Two efficient and effective four sequence designs are discussed in some detail.
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