Impact of Interpatient Pharmacokinetic Variability on Design Considerations for Therapy with Radiolabeled MAbs

Abstract

Radionuclides provide biologically-distributed vehicles for radiotherapy of multifocal cancer. Two algorithms, fixed vs individualized, have been used to prescribe the therapeutic dose of radionuclide (GBq) for the patient. The individualized method for prescribing radionuclide dose takes variations in drug pharmacokinetics into consideration, whereas the fixed method depends, in part, on documentation that there is little interpatient pharmacokinetic variability for the radiolabeled drug. Two data bases, selected to compare iodine-131((131)I) and indium-111((111)In) labeled MAbs, were used to assess interpatient pharmacokinetic variability and its impact on radionuclide dose prescription. Pharmacokinetic data obtained over 7 days for non-Hodgkins lymphoma (NHL) patients given (131)I-Lym-1 (n = 46) or (111)In-Lym-1 (n = 13) were used to obtain cumulated activities. Although (131)I-Lym-1 often showed greater interpatient variability, (111)In-Lym-1 showed several-fold variability for many tissues. Both (131)I- and (111)In-Lym-1 had sufficient interpatient variability to be significant for radionuclide dose prescription, depending on the dose-limiting critical tissue. Interpatient variability exceeded intra- and interoperator variability and intrapatient variability over time for a single institution. In summary, the magnitude of interpatient pharmacokinetic variability for (131)I- and (111)In-Lym-1 suggested that an optimally safe and effective therapy can be best achieved when radionuclide dose is influenced by estimated radiation dose, if the latter is reproducible from institution to institution.

Comparison of Radiation Dose Estimation for Myeloablative Radioimmunotherapy for Relapsed or Recurrent Mantle Cell Lymphoma Using131I Tositumomab to That of Other Types of Non-Hodgkin's Lymphoma

“…20 While myeloablation is to be expected and can be reversed with PBSC, limiting the radiation-absorbed doses to other vital organs by performing organ-specific dosimetry is important to avoid serious organ toxicities. 32,33 Our earlier investigation validating pretherapy dose estimates following trace-labeled antibody with dosimetry after myeloablative therapy found good correlation for the 2 methods. This indicated that the pretherapy estimates can be reliably used to estimate the amount of radioactivity administered.…”

Imaging of the Distribution of 90Y-Ibritumomab Tiuxetan in Bone Marrow and Comparison with Pathology

“…In previous studies, researchers 15 suggested that targeted radiotherapy prescription should be based not only on patient weight basis, but also on dose to tumors and organs at risk. In the same study, they show that a given antibody (Lym-1) labeled with different radionuclides ( 111 In or 131 I) do not exhibit the same uptake.…”

Status of Radioimmunotherapy in the New Millennium

“…Blood and urine clearance studies and measurement of radiation in tissue biopsies have demonstrated that both radioisotopes have similar pharmacokinetics and thus, 111 In can be used to track 90 Y in the same formulation. 36,37 The hepatic retention of radiometal is another disadvantage rendering the liver to be a dose limiting organ and causing a lower therapeutic index than that of the equivalent radioiodinated conjugate. To obviate this problem, a biodegradable linker between the chelated 90 Y and the MAb can be utilized to release the chelated radiometal (discussed later).…”

“…This linker has been shown to halve the hepatic radiation dose in mice and patients when compared to an equivalent nonbiodegradable peptide linker, such as 2-immunothiolane-2-[p-(bromoacetamido) benzyl]-DOTA. 48 DeNardo et al 36 demonstrated a remarkable therapeutic with low radiation dose to the liver in patients with breast cancer. The therapeutic ratio of more than 10:1 for tumor-to-normal tissue, and up to 30:1 for tumor-to-liver was achieved supporting the excellent clinical potential of the peptide linker.…”

“…So far, remissions in solid tumors (e.g., breast, prostate, colon) have been partial, infrequent and short-lived. 36,50,51 The tumor size affects the efficacy of RIT as the RIC uptake usually decreases due to necrosis, increased interstitial pressure (resulting from the lack of functioning lymphatic vessels) and restricted blood supply. 52 This effect is magnified as the tumor size increases.…”