METHODS: Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero.
RESULTS: In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33).
CONCLUSIONS: Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.
CLINICAL PICTURE: A 55-year-old man presented with intermittent low back pain which was progressively worsening, fever, anorexia, low back pain and a 10-kg weight loss. He had underlying diabetes mellitus and ischaemic heart disease. He gave a history of travel to caves for worship. Clinically, the most significant findings included nodular lesions in the anterior fauces and left palatoglossal region. Computed tomographic scan revealed bilateral adrenal masses. Biopsies were taken from the palatal nodules, which revealed histiocytes with numerous histoplasma organisms.
TREATMENT: He was commenced on itraconazole 200 mg daily for a period of 9 months. There was a dramatic initial response with settling of his fever and this was followed by subjective improvement in his well-being.
OUTCOME: He is presently on follow-up and has completed 9 months of itraconazole therapy with resolution of all his symptoms and has gained about 10 kg of weight.