Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours.

AIM: To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. METHODS: This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. RESULTS: In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC0-24 increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib Cmax increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %). CONCLUSIONS: Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.

Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.

AIMS: To characterize the impact of potent CYP3A4 inhibition and induction on lapatinib pharmacokinetics. METHODS: Two studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.i.d. for 7 days on a single 100-mg dose of lapatinib in 22 healthy subjects. The other study examined the effect of carbamazepine titrated up to 200 mg b.i.d. over 20 days on a single 250-mg dose of lapatinib in 24 healthy subjects. RESULTS: Ketoconazole altered lapatinib AUC, C(max) and half-life, with geometric mean [95% confidence interval (CI)] increases of 3.57-fold (3.07, 4.15), 2.14-fold (1.74, 2.64) and 1.66-fold (1.50, 1.84), respectively, but had no effect on absorption rate. Carbamazepine altered lapatinib AUC, C(max) and absorption rate, with geometric mean (95% CI) decreases of 72% (68, 77), 59% (49, 66) and 28% (4, 46), respectively, but had no effect on half-life. CONCLUSIONS: Systemic exposure to lapatinib was significantly altered by potent inhibition and induction of CYP3A4. Dose adjustments may be required when lapatinib is administered with orally administered drugs that potently alter the activity of this enzyme.

A phase I and pharmacokinetic study of lapatinib in combination with letrozole in patients with advanced cancer.

PURPOSE: The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. RESULTS: Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (>25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (C(max) and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response. CONCLUSIONS: Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.

Mid upper arm circumference as a predictor of risk of mortality in children in a low resource setting in India.

OBJECTIVE: In this secondary analysis of data from an intervention trial, we assessed the performance of Mid Upper Arm Circumference (MUAC) as a predictor of mortality in children aged 6-59 months from Delhi, India, one year after their initial MUAC measurements were taken. Additionally, we assessed MUAC as an absolute value and MUAC z-scores as predictors of risk of mortality. METHODS: In the trial, children were screened using MUAC prior to referral to the study clinic. These children were revisited a year later to ascertain their vital status. Baseline MUAC and MUAC z-scores were used to categorize children as severely (MUAC <115 mm, MUAC z-score <-3SD) or moderately (MUAC 115 to <125 mm, MUAC z-score <-2SD) malnourished. The proportion of malnutrition, risk of mortality, relative risk estimates, positive predictive value and area under the curve (AUC) by MUAC and MUAC z-scores were calculated. RESULTS: In the resurvey, the first 36159 children of the 48635 in the initial survey were contacted. Of these, vital status of 34060 (94.2%) was available. The proportion of severe malnutrition by MUAC (<115 mm) was 0.5% with an associated mortality of 4.7% over a one year period and an attributable mortality of 13% while the proportion of the severe malnutrition by MUAC z-score (<-3SDwas 0.9% with an associated mortality of 2.2%. CONCLUSIONS: MUAC is a significant predictor of subsequent mortality in under-five children. In settings where height measurement is not feasible, MUAC can be used as a screening tool for identifying severely malnourished children for management.

The effects of lapatinib on CYP3A metabolism of midazolam in patients with advanced cancer.

PURPOSE: The potential inhibition of CYP3A4 by lapatinib was studied using midazolam as a probe substrate in patients with cancer. METHODS: This was a partially randomized, 4-period, 4-sequence, 4-treatment, cross-over study in 24 patients with advanced cancer. Single 1-mg IV and 3-mg oral doses of midazolam were given 2 days apart, in a partially random order, on study days 1, 3, 9, and 11. Lapatinib 1500-mg was administered orally once daily on study days 4 through 11. Midazolam plasma concentrations were measured up to 24-h post dosing, and lapatinib plasma concentrations measured prior to each midazolam dose. RESULTS: Lapatinib increased the geometric mean (95% CIs) midazolam AUC(o-∞) by 45% (31-60%) after the oral dose and by 14% (0-29%) after the IV dose, and prolonged the midazolam elimination half-life by 48% (22-81%) after the oral dose and by 20% (2-40%) after the IV dose. Lapatinib decreased midazolam total clearance by 13% (1-23%), while total bioavailability was increased 23% (4-46%) without changes in apparent volume of distribution or hepatic bioavailability. CONCLUSION: These data show that lapatinib caused weak inhibition of gastrointestinal CYP3A4 in vivo. This suggests that oral CYP3A4 drug substrates with a narrow therapeutic index may need dose reduction if lapatinib is to be co-prescribed.

Effect of lapatinib on oral digoxin absorption in patients.

The potential for an interaction between lapatinib and absorption of the P-glycoprotein (ABCB1) substrate digoxin at a therapeutic dose in breast cancer patients was characterized. Seventeen women with HER2-positive metastatic breast cancer received a single oral 0.5-mg dose of digoxin on days 1 and 9 and oral lapatinib 1500 mg once daily on days 2 through 9. Digoxin pharmacokinetic parameters were determined on day 1 (digoxin administration alone) and on day 9 (coadministration of lapatinib and digoxin), and parameters were compared to determine the effects of lapatinib on digoxin absorption. Concomitant medications that could affect ABCB1 were accounted for. Lapatinib 1500 mg/day increased digoxin absorption approximately 80%, implicating lapatinib inhibition of intestinal ABCB1-mediated efflux. In summary, coadministration of lapatinib with narrow therapeutic index drugs that are substrates of ABCB1 should be undertaken with caution and dose adjustment should be considered.

Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer.

PURPOSE: This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors. PATIENTS AND METHODS: Doses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level. RESULTS: Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m(2) (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients (>or= 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately. CONCLUSION: The combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.

Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer.

PURPOSE: The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer. PATIENTS AND METHODS: Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination. RESULTS: A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone. CONCLUSION: The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies.

PURPOSE: This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. RESULTS: Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m(2)/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and alpha-fluoro-beta-alanine, were not meaningfully altered by coadministration. CONCLUSION: Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.