Paclitaxel + Valspodar

Paclitaxel + valspodar is a combination therapy that has been studied in clinical trials for various cancer types, particularly focusing on overcoming multidrug resistance in cancer treatment. This combination pairs paclitaxel, a widely used chemotherapeutic agent, with valspodar (also known as PSC 833), which is a P-glycoprotein inhibitor designed to prevent cancer cells from pumping out chemotherapy drugs.\n\n## Mechanism and Development\n\nValspodar is a non-immunosuppressive cyclosporine D analogue that works by inhibiting P-glycoprotein, a membrane transporter that can pump drugs out of cells, contributing to multidrug resistance in cancer[1][4]. By blocking this mechanism, valspodar aims to increase the intracellular concentration of paclitaxel, potentially enhancing its efficacy against resistant tumors[7].\n\nWhen administered together, valspodar significantly alters the pharmacokinetics of paclitaxel. This interaction necessitates a reduction in paclitaxel dosage (typically by 30-60%) when given with valspodar to maintain acceptable toxicity profiles[1][3]. Studies have shown that reduced doses of paclitaxel (around 40% of standard dose) with valspodar produce comparable pharmacokinetic profiles to full-dose paclitaxel alone[1][4].\n\n## Clinical Trials and Efficacy\n\nMultiple clinical trials have evaluated this combination:\n\n- Phase I trials established that paclitaxel at 70 mg/m² (40% of standard dose) with valspodar 5 mg/kg orally four times daily was safe and produced toxicity profiles comparable to full-dose paclitaxel alone[1][4].\n\n- A Phase II study in paclitaxel-resistant ovarian cancer showed limited activity with only 8.6% of patients achieving partial responses[6].\n\n- A Phase III trial in untreated patients with advanced ovarian or primary peritoneal cancer found that adding valspodar to paclitaxel and carboplatin did not improve time to progression or overall survival compared to standard therapy, while increasing toxicity[2].\n\n## Toxicity Profile\n\nThe most significant adverse events associated with this combination include:\n\n- Hematologic toxicities, particularly myelosuppression and neutropenia, which were dose-limiting[1][3].\n- Neurologic toxicities including ataxia and paresthesias[2][4].\n- Gastrointestinal toxicities[2].\n- Hepatic toxicities including hyperbilirubinemia and transaminitis[4].\n\n## Current Status\n\nDespite promising preclinical rationale, the clinical development of valspodar in combination with paclitaxel has been largely discontinued due to limited efficacy in clinical trials and the development of alternative approaches to overcome drug resistance[4]. However, the concept of transporter inhibition to enhance chemotherapy efficacy continues to be explored in other contexts, including with antibody-drug conjugates[4].\n\nThe combination demonstrated particular promise in preclinical studies for enhancing paclitaxel penetration across the blood-brain barrier, potentially improving treatment of brain tumors[7].

Other names

paclitaxel + PSC 833