The use of PET/CT imaging data for a mechanistic PK model of radiolabeled temozolomide.

Abstract

Background Temozolomide is a chemotherapeutic drug that is currently dosed according to the body surface area (BSA) in malignant gliomas. Although effective, many patients stop prematurely due to early tumor progression or treatment-related hematological toxicity. Factors that contribute to treatment efficacy and toxicity in individual patients are unclear, but variable tumor penetration has been proposed. To optimize treatment, describing the pharmacokinetics (PK) of temozolomide, including tumor tissue penetration, is essential. A prior microdosed 11C-temozolomide PET(CT) allowed us to visualize tumor uptake in two glioblastoma patients. Building on these preliminary data, we now aimed to assess whether a pilot PET(CT)-PK study, combined with a larger PK study with temozolomide is feasible in order to optimize therapeutic responsess of temozolomide in patients with glioblastoma.

Methods First, we performed a literature search to predict linearity among microdose and therapeutic dose levels. We studied the PK-profile of temozolomide and its’ metabolites to form a semi-mechanistic PK modeling plan. Then, the preliminary 11C-temozolomide PET/CT patient data were analyzed, aiming to assess feasibility of using PET/CT to quantify tumor penetration. Finally, a clinical study protocol was developed for evaluation of temozolomide PK.

Results As substrate for multiple drug transporters and albumin binding proteins, temozolomide is unlikely to have linear PK among dose levels in all tissues. Temozolomide is a prodrug that degrades spontaneously, forming a methyl diazonium ion. This active compound methylates DNA. The proposed model to assess PK semi-mechanistically consists of a peripheral, central and brain compartment, in which temozolomide can occur unbound, bound or converted to a DNA adduct.

Preliminary 11C-temozolomide PET and blood samples (SPE derived) data-analyses enabled quantification. However, due to its’ spontaneous degradation, the blood samples - obtained using standard PET-procedures - were not suitable to distinguish temozolomide from metabolites and active DNA adducts.

The developed study protocol has an innovative approach, in which one therapeutic dose is administered prior to the micro-dosed tracer and PET/CT is combined with LC-MS sample analyses to distinguish temozolomide, metabolites and DNA adducts in blood and tumor tissues. PK-findings of this study will be used to predict PK in a large population to assess the exposure-response association in a multicenter study. This could ultimately lead to dose individualization to promote efficacy and prevent toxicity.

Conclusions This study demonstrates that clinical pharmacology, pharmaceutic and PET tracer knowledge should be combined when developing tracer studies with complex molecules. Innovative methods, combining LC-MS with PET imaging, are feasible. The proposed study may improve glioblastoma treatment and provide new insights to optimize small molecule PET(CT) studies.