[Sympathomimetic syndrome caused by autointoxication with methylphenidate]. / Sympathicomimetisch syndroom door auto-intoxicatie met methylfenidaat.

A 31-year-old man claimed that he had ingested more than 100 tablets of methylphenidate (10 mg), 20 tablets ofibuprofen (400 mg) and 2 bottles of wine. At admission, signs of sympathomimetic syndrome were observed, including agitation, hallucinations, mydriasis and sinus tachycardia. The patient was treated with activated charcoal and an oral laxative. Given the possibly lethal dose of methylphenidate, the patient was admitted to the intensive care unit for observation. He made a full recovery and was discharged 36 hours after admission. Toxicological analysis indicated a plasma-ethanol concentration of 0.27% and a maximum serum-methylphenidate concentration of 176 microg/l (therapeutic range: 5-40 microg/l). The active metabolite ethylphenidate was also present at toxic concentrations. Treatment of potentially lethal methylphenidate poisoning includes prevention of absorption, careful observation and support of vital functions as necessary.

Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel.

PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4. PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m(2) with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m(2). RESULTS: The mean (+/- SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m(2) without CsA was 0.37 +/- 0.33 mg.h/L and 2.71 +/- 1.81 mg.h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m(2) was 4.41 +/- 2.10 mg.h/L. The absolute bioavailability of oral docetaxel was 8% +/- 6% without and 90% +/- 44% with CsA. The oral combination of docetaxel and CsA was well tolerated. CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

Phase I and pharmacokinetic study of oral paclitaxel.

PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m(2) as a 3-hour infusion. RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m(2). Dose escalation of oral paclitaxel from 60 to 300 mg/m(2) resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values +/- SD after 60, 180, and 300 mg/m(2) of oral paclitaxel were 1.65 +/- 0.93, 3.33 +/- 2.39, and 3.46 +/- 1.37 micromol/L.h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 +/- 3.26 micromol/L.h. CONCLUSION: The MTD of oral paclitaxel was 300 mg/m(2). However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m(2), the oral paclitaxel dose of 180 mg/m(2) in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.

Coadministration of oral cyclosporin A enables oral therapy with paclitaxel.

i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremophor EL. Oral administration may be attractive because it may circumvent the use of Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs, has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug efflux pump, which is abundantly present in the gastrointestinal tract. Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its major metabolites were determined during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tolerated and did not induce gastrointestinal toxicity or myelosuppression. Cremophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.

A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A.

PURPOSE: To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination. PATIENTS AND METHODS: A total of 15 patients received during course 1 two doses of oral paclitaxel (2 x 60, 2 x 90, 2 x 120, or 2 x 160 mg/m2) 7 h apart in combination with 15 mg/kg of cyclosporin A, co-administered to enhance the absorption of paclitaxel. During subsequent courses, patients received 3-weekly intravenous paclitaxel at a dose of 175 mg/m2 as a 3-h infusion. RESULTS: Toxicities observed following b.i.d. dosing of oral paclitaxel were generally mild and included toxicities common to paclitaxel administration and mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea, which occurred more often at the higher dose levels. Dose escalation of b.i.d. oral paclitaxel from 2 x 60 to 2 x 160 mg/m2 did not result in a significant increase in the area under the plasma concentration-time curve (AUC) of paclitaxel. The AUC after doses of 2 x 60, 90, 120, and 160 mg/m2 were 3.77 +/- 2.70, 4.57 +/- 2.43, 3.62 +/- 1.58, and 8.58 +/- 7.87 microM.h, respectively. The AUC achieved after intravenous administration of paclitaxel 175 mg/m2 was 17.95 +/- 3.94 microM.h. CONCLUSION: Dose increment of paclitaxel did not result in a significant additional increase in the AUC values of the drug. Dose escalation of the b.i.d. dosing regimen was therefore not continued up to DLT. As b.i.d. dosing appeared to result in higher AUC values compared with single-dose administration (data which we have published previously), we recommend b.i.d. dosing of oral paclitaxel for future studies. Although pharmacokinetic data are difficult to interpret, due to the limited number of patients at each dose level and the large interpatient variability, we recommend the dose level of 2 x 90 mg/m2 for further investigation, as this dose level showed the highest systemic exposure to paclitaxel combined with good safety.

Modulation of oral bioavailability of anticancer drugs: from mouse to man.

Oral bioavailability of many anticancer drugs is poor and highly variable. This is a major impediment to the development of new generation drugs in oncology, particularly those requiring a chronic treatment schedule, a.o. the farnesyltransferase inhibitors. Limited bioavailability is mainly due to: (1) cytochrome P450 (CYP) activity in gut wall and liver, and (2) drug transporters, such as P-gp in gut wall and liver. Shared substrate drugs are affected by the combined activity of these systems. Available preclinical in vitro and in vivo models are in many cases only poorly predictive for oral drug uptake in patients because of a.o. interspecies differences in CYP drug metabolism and intestinal drug-transporting systems. Clearly, novel systems that allow reliable translation of preclinical results to the clinic are strongly needed. Our previous work, also using P-gp knockout (KO) mice, already showed that P-gp has a major effect on the oral bioavailability of several drugs and that blockers of P-gp can drastically improve oral bioavailability of paclitaxel and other drugs in mice and humans (Schinkel et al., Cell 77 (1994) 491; Sparreboom et al., Proc. Natl. Acad, Sci. USA 94 (1997) 2031; Meerum Terwogt et al. Lancet 352 (1998) 285). This work revealed, however, that apart from P-gp other drug-transporting systems and CYP effects also determine overall oral drug uptake. The taxanes paclitaxel and docetaxel are considered excellent substrate drugs to test the concept that by inhibition of P-gp in the gut wall and CYP activity in gut wall and/or liver low oral bioavailability can be increased substantially. In current studies we focus on the development of chronic oral treatment schedules with these drugs and on other drug transport systems that may play a significant role in regulation of oral bioavailability of other classes of (anti-cancer) drugs. The current review paper describes the background and summarizes our recent results of modulation of oral bioavailability of poorly available drugs, focused on drug transport systems and CYP in gut wall and liver.

Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.

INTRODUCTION: Erlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD. METHODS: Our case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature. RESULTS: Besides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high. CONCLUSION: Erlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.

Oral delivery of taxanes.

Oral treatment with cytotoxic agents is to be preferred as this administration route is convenient to patients, reduces administration costs and facilitates the use of more chronic treatment regimens. For the taxanes paclitaxel and docetaxel, however, low oral bioavailability has limited development of treatment by the oral route. Preclinical studies with mdr1a P-glycoprotein knock-out mice, which lack functional P-glycoprotein activity in the gut, have shown significant bioavailability of orally administered paclitaxel. Additional studies in wild-type mice revealed good bioavailability after oral administration when paclitaxel was combined with P-glycoprotein blockers such as cyclosporin A or the structurally related compound SDZ PSC 833. Based on the extensive preclinical research, the feasibility of oral administration of paclitaxel and docetaxel in cancer patients was recently demonstrated in our Institute. Co-administration of cyclosporin A strongly enhanced the oral bioavailability of both paclitaxel and docetaxel. For docetaxel in combination with cyclosporin A an oral bioavailability of 90% was achieved with an interpatient variability similar to that after intravenous drug administration; for paclitaxel the oral bioavailability is estimated at approximately 50%. The safety of the oral route for both taxanes is good. A phase II study of weekly oral docetaxel in combination with cyclosporin A is currently ongoing.

Cyclosporine-induced anaphylaxis.

OBJECTIVE: To describe a case of an anaphylactic reaction after first ingestion of oral cyclosporine capsules (Neoral). CASE SUMMARY: A 73-year-old white woman was admitted for the treatment of metastatic breast carcinoma with an experimental oral paclitaxel solution in combination with cyclosporine capsules. After ingestion of the cyclosporine capsules, the patient collapsed within one hour. She initially experienced severe hypotension and bradycardia. After a few minutes, she developed severe tachycardia, dyspnea, and decreased consciousness. Administration of epinephrine, dexamethasone, clemastine, oxygen, and gelofusine (succinylated gelatin 4% in NaCl 0.9%) infusion resulted in complete recovery after several hours. The planned oral paclitaxel administration was canceled. Intravenous paclitaxel was given the next day, preceded by standard premedication with dexamethasone, clemastine, and cimetidine, without complications. DISCUSSION: To our knowledge, this is the first report in the literature of an anaphylactic reaction after oral ingestion of cyclosporine capsules. Earlier reports of anaphylaxis concerned intravenous cyclosporine or oral solutions of cyclosporine (both Sandimmune). These anaphylactic reactions were considered to be due to the pharmaceutical vehicle Cremophor EL or related substances, which are well-known causes of anaphylaxis. The capsules used in this case contain the Cremophor EL-related polyoxyl 40 hydrogenated castor oil as a base; our patient's anaphylactic shock may have been due to this substance. CONCLUSIONS: In addition to earlier reports about anaphylactic reactions after administration of an intravenous or oral solution of cyclosporine, this case shows that anaphylactic shock can occur after ingestion of cyclosporine capsules.

Pharmacokinetics of oral cyclosporin A when co-administered to enhance the absorption of orally administered docetaxel.

OBJECTIVE: To evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the absorption of orally administered docetaxel. METHODS: Patients (n = 9) with histological proof of solid cancer received oral docetaxel 75 mg/m2 in combination with oral CsA 15 mg/kg. RESULTS: The area under the blood concentration-time curve (AUC) of CsA when combined with docetaxel 75 mg/m2 was 31.0+/-9.3 mg/l h (mean +/- SD). Compared with literature data of the same dose of CsA, AUC values in our study appear to be substantially higher. In addition, compared with the AUC values of CsA in combination with oral paclitaxel (previously published data), AUC values in this study are approximately 1.5-fold higher. CONCLUSIONS: The higher AUC values of CsA obtained in this study compared with literature data may be explained by competitive inhibition of cytochrome P450 (CYP) 3A4-mediated metabolism of CsA by docetaxel. In addition, the higher levels of CsA with docetaxel than with paclitaxel co-administration may be explained by the fact that docetaxel is almost exclusively metabolised by CYP 3A4, whereas paclitaxel is predominantly metabolised by CYP 2C8 and to a lesser extent by CYP 3A4.

Pharmacokinetics of oral cyclosporin A when co-administered to enhance the oral absorption of paclitaxel.

The objective of this study was to evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the oral absorption of paclitaxel. Patients received oral paclitaxel in doses of 60-360 mg/m(2) in combination with a dose of oral CsA of 15 mg/kg. Dose escalation of paclitaxel from 60 to 300 mg/m(2) resulted in a significant decrease in the area under the concentration-time curve (AUC) of CsA from 24.4+/-9.9 to 17.6+/-2.8 mg/l.h (p=0.03) (n=28). In conclusion, increases in the paclitaxel dose resulted in a decrease in the AUC of CsA. This observation may be explained by the increase in the co-solvent Cremophor EL of paclitaxel causing reduced absorption of CsA.

Metabolism and excretion of paclitaxel after oral administration in combination with cyclosporin A and after i.v. administration.

The objective of this study was to compare the quantitative excretion of paclitaxel and metabolites after i.v. and oral drug administration. Four patients received 300 mg/m2 paclitaxel orally 30 min after 15 mg/kg oral cyclosporin A, co-administered to enhance the uptake of paclitaxel. Three weeks later these and three other patients received 175 mg/m2 paclitaxel by i.v. infusion. Blood samples, urine and feces were collected up to 48-96 h after administration, and analyzed for paclitaxel and metabolites. The area under the plasma concentration-time curve of paclitaxel after i.v. administration (175 mg/m2) was 16.2 +/- 1.7 microM x h and after oral administration (300 mg/m2) 3.8 +/- 1.5 microM x h. Following i.v. infusion of paclitaxel, total fecal excretion was 56 +/- 25%, with the metabolite 6alpha-hydroxypaclitaxel being the main excretory product (37 +/- 18%). After oral administration of paclitaxel, total fecal excretion was 76 +/- 21%, of which paclitaxel accounted for 61 +/- 14%. In conclusion, after i.v. administration of paclitaxel, excretion occurs mainly in the feces with the metabolites as the major excretory products. Orally administered paclitaxel is also mainly excreted in feces but with the parent drug in highest amounts. We assume that this high amount of parent drug is due to incomplete absorption of orally administered paclitaxel from the gastrointestinal tract.

Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients.

Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m(2)in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m(2)as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration-time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 +/- 1.67 microM x h. In our previously performed study of 120 mg/m(2)oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 +/- 2.29 microM x h. After i.v. administration of paclitaxel the mean AUC was 15.92( )+/- 2.46 microM x h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel.

The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients.

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel

The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel.

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m(2) oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 microM (T>0.1 microM) of oral paclitaxel. The mean (+/-SD) AUC and T>0.1 microM values of oral paclitaxel with CsA 10 mg/kg were 4.29+/-0.88 microM x h and 12.0+/-2.1 h, respectively. With CsA 5 mg/kg these values were 2.75+/-0.63 microM x h and 7.0+/-2.1 h, respectively (p=0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 microM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 microM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.