Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175–3 h = 42.8 ± 24.9 ml h−1 m−2; Cl175–24 h = 79.7 ± 24.3; P = 0.035 and Cl135–3 h = 44.1 ± 21.8 ml h−1 m−1; Cl140–96 h = 211.8 ± 32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics–pharmacodynamics relationships. © 1999 Cancer Research Campaig

Prognostic Value of Bone Scintigraphy in Cancer Patients With Osteonecrosis of the Jaw

identifying imaging predictors of healing of osteonecrosis of the jaw (ONJ) in cancer patients may assist in better stratification of treatment strategies. MATERIALS AND METHODS: patients with ONJ were followed prospectively and underwent bone scintigraphy, both planar and single-photon emission computed tomography (SPECT) imaging. End points were time to healing and the number of recurrences. Studied parameters included lesion visibility, pattern of uptake, and quantification of uptake relative to the unaffected side. RESULTS: a total of 22 patients were recruited (3 men; 19 women) with a stage 1 ONJ lesion in 8, stage 2 in 9, and stage 3 ONJ in 5 patients. Median duration of follow-up was 12 months (range, 6-37). SPECT acquisitions proved superior over planar images in detecting ONJ lesions (P = 0.03). Quantification of tracer uptake in the ONJ lesion relative to the unaffected side showed increasing uptake with higher stages of ONJ: mean, 1.67 (95% confidence interval [CI], 1.17-2.18) in stage 1, 2.72 (95% CI, 2.24-3.20) in stage 2, and 4.62 (95% CI, 3.98-5.26) in stage 3. In addition, this relative ratio of uptake was found to be an independent predictor of ONJ healing (hazard ratio, 0.24; 95% CI, 0.07-0.82; P = 0.02). Neither ONJ stage nor relative ratio of uptake were predictors of the occurrence of ONJ relapses. CONCLUSIONS: bone scintigraphy in patients with ONJ is feasible and SPECT acquisitions are preferred over planar images. Relative quantification of tracer uptake provides prognostic information independent of clinical stage that may assist in identifying patients with a poor prognosis

Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice

The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol. Its oral bioavailability is very low due to the action of P-glycoprotein in the gut wall and CYP450 in gut wall and liver. However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed. We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF’s) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF’s without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself. Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor EL-ethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF’s maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels

High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection

BACKGROUND: The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy. METHODS: Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel. RESULTS: The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within ± 15%, except at the limit of quantitation where values within ± 20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m(2 )of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion. CONCLUSION: We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase

Phase I study of dose-escalated paclitaxel, ifosfamide, and cisplatin (PIC) combination chemotherapy in advanced solid tumours

Based on the already known in vitro synergy between paclitaxel (taxol), cisplatin and oxazophosphorine cytostatics and the broad spectrum of activity of the above drugs we sought to evaluate the paclitaxel (taxol)-ifosfamide-cisplatin (PIC) combination in the outpatient setting in individuals with a variety of advanced solid tumours. Cohorts of patients were entered into six successive dose levels (DLs) with drug doses ranging as follows: paclitaxel 135–215 mg m−2day 1 – (1 h infusion), ifosfamide 4.5–6.0 g m−2(total dose) – divided over days 1 and 2, and cisplatin 80–100 mg m−2(total) – divided over days 1 and 2. Granulocyte colony-stimulating factor was given from day 5 to 14. Forty-two patients were entered. Eighteen patients had 2–8 cycles of prior chemotherapy with no taxanes or ifosfamide (cisplatin was allowed). The regimen was tolerated with outpatient administration in 36/42 patients. Toxicities included: grade 4 neutropenia for ≤ 5 days in 27% of cycles; 5 episodes of febrile neutropenia in three patients at DL-III, -V and -VI. Grade 3/4 thrombocytopenia and cumulative grade 3 anaemia were seen in 7% and 13% of cycles respectively. Three cases of severe grade 3 neuromotor/sensory neuropathy were recorded at DL-II, -III, and -V, all after cycle 3. The maximum tolerated dose was not formally reached at DL-V, but because of progressive anaemia and asthenia/fatigue, it was decided to test a new DL-VI with doses of paclitaxel 200 mg m−2, ifosfamide 5.0 g m−2and cisplatin 100 mg m−2; this appeared to be tolerable and is recommended for further phase II testing. The response rate was 47.5% (complete response + partial response: 20/42). The PIC regimen appears to be feasible and safe in the outpatient setting. Care should be paid to neurotoxicity. Phase II studies are starting in non-small-cell lung cancer, ovarian cancer and head and neck cancer at DL-VI. © 2000 Cancer Research Campaig

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6 pmol min−1 mg−1. The Km of the tumoral enzyme (42±8 μM) is similar to that in healthy colorectal epithelium (36±8 μM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2 pmol min−1 mg−1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs

Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor ciclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m−2 combined with CsA 10 mg kg−1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m−2 week−1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer

Interstitial lung disease in children - genetic background and associated phenotypes

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice