Validation of Population Pharmacokinetic Models for Clozapine Dosage Prediction.

BACKGROUND: Clozapine is unique in its capacity to ameliorate severe schizophrenia but at high risk of toxicity. A relationship between blood concentration and clinical response and evidence for concentration-response relationships to some adverse effects justify therapeutic drug monitoring of clozapine. However, the relationship between drug dose and blood concentration is quite variable. This variability is, in part, due to inductive and inhibitory interactions varying the activity of cytochrome P450 1A2 (CYP1A2), the principal pathway for clozapine elimination. Several population pharmacokinetic models have been presented to facilitate dose selection and to identify poor adherence in individual patients. These models have faced little testing for validity in independent populations or even for persisting validity in the source population. METHODS: Therefore, we collected a large population of clozapine-treated patients (127 patients, 1048 timed plasma concentrations) in whom dosing and covariate information could be obtained with high certainty. A population pharmacokinetic model was constructed with data collected in the first 6 weeks from study enrolment (448 plasma concentrations), to estimate covariate influences and to allow alignment with previously published models. The model was tested for its performance in predicting the concentrations observed at later time intervals up to 5 years. The predictive performances of 6 published clozapine population models were then assessed in the entire population. RESULTS: The population pharmacokinetic model based on the first 6 weeks identified significant influences of sex, smoking, and cotreatment with fluvoxamine on clozapine clearance. The model built from the first 6 weeks had acceptable predictive performance in the same patient population up to the first 26 weeks using individual parameters, with a median predictive error (PE) of -0.1% to -15.9% and median absolute PE of 22.9%-27.1%. Predictive performance fell progressively with time after 26 weeks. Bayesian addition of plasma concentration observations within each prediction period improved individual predictions. Three additional observations extended acceptable predictive performance into the second 6 months of therapy. When the published models were tested with the entire data set, median PE ranged from -8% to +35% with a median absolute PE of >39% in all models. Thus, none of the tested models was successful in external validation. Bayesian addition of single patient observations improved individual predictions from all models but still without achieving acceptable performances. CONCLUSIONS: We conclude that the relationship between covariates and blood clozapine concentrations differs between populations and that relationships are not stable over time within a population. Current population models for clozapine are not capturing influential covariates.

A rare case of vertebral osteomyelitis with associated epidural abscess complicating BCG immunotherapy for transitional cell carcinoma of the bladder.

Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis was first described as a vaccine against tuberculosis in 1921. The use of intravesical BCG to treat non-muscle invasive bladder cancer (NMIBC) was first described by Morales in 1921. The therapeutic effect of BCG is related to stimulation of the immune system following direct contact with tumour cells. As a result of this intended immune response some minor symptoms including fever, malaise and bladder irritation manifesting as dysuria, urinary frequency and mild haematuria, are expected. These side effects are however, generally easily managed and well tolerated. Severe complications are rare and can be temporally remote from the instillation of therapy. In this report we describe the case of a 74-year-old immunocompetent man with biopsy confirmed BCG T11/12 discitis and adjacent osteomyelitis of the T11/T12 vertebral bodies with an associated an epidural abscess following intravesical administration of BCG therapy for recurrent bladder transitional cell carcinoma (TCC).

Isolated Anemia in a 69-Year-Old Man with HIV-1: Features of Pure Red Cell Aplasia Mediated by Chronic Parvovirus-B19 Infection.

BACKGROUND Pure red cell aplasia (PRCA) is an uncommon syndrome characterized by ineffective erythropoiesis and severe anemia. Among immunodeficient patients, including those with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), persistent parvovirus-B19 can cause PRCA. We report a rare case of an Australian man with parvovirus-B19 mediated PRCA secondary to a new diagnosis of HIV-1/AIDS. The case highlights the importance of early treatment initiation with anti-retroviral drugs and pooled immunoglobulins to enable marrow recovery and long-term disease remission. CASE REPORT A 64-year-old man residing in rural Indonesia presented with severe anemia. Apart from 8 kg of unintentional weight loss, he denied any occult bleeding, diatheses, or constitutional symptoms. His bloodwork revealed a normocytic, normochromic anemia (Hb 81 g/L) with profound reticulocytopenia (9.5×109/L). Parvovirus-B19 serology and polymerase chain reaction testing confirmed active viremia. Lymphopenia and an undetectable CD4 T-lymphocyte count (<1%) were also noted; HIV-1 was subsequently diagnosed. Bone marrow sampling later confirmed features consistent with parvovirus-B19-driven PRCA secondary to HIV-1/AIDS. The patient received 1 g/kg intravenous immunoglobulin for two days and initiated anti-retroviral HIV therapy. Rapid reticulocytosis with slow incrementation of his hemoglobin were observed over one month. At three years following his diagnosis, he remains in remission. CONCLUSIONS Severe, isolated anemia in immunodeficient patients, particularly those with HIV-1/AIDS, should prompt consideration of parvovirus-B19-mediated PRCA. Depletion of CD4-T-lymphocyte populations enables the establishment of parvovirus-B19 reservoirs within erythroid progenitors, thereby hampering physiological erythropoiesis. Long-term remission can be achieved with the rapid institution of intravenous immunoglobulin and anti-retroviral HIV therapies.