Certus

Lapatinib is a 4-anilinoquinazoline kinase inhibitor. It acts on the intracellular tyrosine kinase domains of two receptors: Epidermal Growth Factor Receptor (EGFR [ErbB1]) and Human Epidermal Receptor Type 2 (HER2 [ErbB2]). The estimated Kiapp values are 3nM and 13nM, respectively, and the dissociation half-life is greater than or equal to 300 minutes. In the laboratory and in several animal models, Lapatinib inhibits the growth of ErbB-driven tumor cells. An in vitro study tested Lapatinib together with 5-FU (the active metabolite of Capecitabine) in 4 tumor cell lines, and the combination showed an additive effect. The growth inhibitory effects of Lapatinib were also checked in Trastuzumab-conditioned cell lines. Lapatinib kept significant activity against breast cancer cell lines that had been selected for long-term growth in Trastuzumab-containing medium in vitro. These findings suggest there is no cross-resistance between the two agents. Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that also coexpress HER2 tend to be resistant to established endocrine therapies. In the same way, hormone receptor-positive breast cancer cells that start out lacking EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.

Absorption: When Lapatinib is taken by mouth, absorption is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours), and peak plasma concentrations (Cmax) come about 4 hours after the dose. With daily dosing, steady state is reached within 6 to 7 days, which points to an effective half-life of 24 hours. At a dose of 1,250 mg daily, the steady-state geometric mean [95% confidence interval (CI)] values were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) for Cmax and 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL) for AUC. When the daily dose was divided, exposure at steady state (steady-state AUC) was approximately 2-fold higher than when the same total dose was given once daily. Food raises systemic exposure to Lapatinib. With a lowfat meal (5% fat-500 calories), AUC values were approximately 3-fold higher and Cmax approximately 2.5-fold higher. With a high-fat meal (50% fat-1,000 calories), AUC values were approximately 4-fold higher and Cmax approximately 3-fold higher.

Distribution: Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that it is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.

Metabolism: Lapatinib is extensively metabolised, mainly by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8. This produces several oxidated metabolites. None of them accounts for more than 14% of the dose recovered in the feces or 10% of Lapatinib concentration in plasma.

Elimination: At clinical doses, the terminal phase half-life after a single dose was 14.2 hours, and accumulation with repeated dosing indicates an effective half-life of 24 hours. Lapatinib is cleared mostly by metabolism through CYP3A4/5, and renal excretion is negligible (less than 2%). Unchanged Lapatinib recovered in the feces accounts for a median of 27% (range 3% to 67%) of an oral dose.

Animal studies and the way Lapatinib works suggest it can harm an unborn baby if a pregnant woman takes it. There are no human data to show what the actual risk is. Pregnant women, and women who could become pregnant, should be told about the possible risk to the baby.

No one knows whether Lapatinib passes into human milk, or what it does to a breastfed child or to milk production. Because a breastfed child could have serious adverse reactions from it, women who are breastfeeding should not breastfeed during treatment with Lapatinib and for 1 week after the last dose.

Dose modification guidelines

Cardiac events: Lapatinib should be stopped in patients whose left ventricular ejection fraction (LVEF) has fallen to Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0), and in patients whose LVEF drops below the institution's lower limit of normal (LLN) and Adverse Reactions (6.1)]. After a minimum of 2 weeks, Lapatinib can be restarted if the LVEF has recovered to normal and the patient has no symptoms. With Capecitabine the restart dose is reduced (1,000 mg/day), and with Letrozole it is 1,250 mg/day.

Hepatic impairment: Patients with severe hepatic impairment (Child-Pugh Class C) should have their Lapatinib dose reduced. For the HER2-positive metastatic breast cancer indication, the dose goes from 1,250 mg/day to 750 mg/day. For the hormone receptor-positive, HER2-positive breast cancer indication, it goes from 1,500 mg/day to 1,000 mg/day. This reduction is predicted to bring the area under the curve (AUC) into the normal range and should be considered. There are no clinical data with this dose adjustment in patients with severe hepatic impairment, however.

Diarrhea: Lapatinib should be interrupted if diarrhea is NCI CTCAE Grade 3, or Grade 1 or 2 with complicating features. These features are moderate to severe abdominal cramping, nausea or vomiting of NCI CTCAE Grade 2 or greater, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration. Once the diarrhea settles to Grade 1 or less, Lapatinib may be started again at a lower dose (1,250 mg/day reduced to 1,000 mg/day, or 1,500 mg/day reduced to 1,250 mg/day). TYKERB should be stopped permanently in patients with NCI CTCAE Grade 4 diarrhea.

Concomitant strong CYP3A4 inhibitors: Strong CYP3A4 inhibitors should be avoided with Lapatinib (e.g., Ketoconazole, Itraconazole, Clarithromycin, Atazanavir, Indinavir, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, Voriconazole). Grapefruit may also raise plasma concentrations of Lapatinib, so it should be avoided too. If a strong CYP3A4 inhibitor must be given together with it, pharmacokinetic studies predict that a Lapatinib dose of 500 mg/day would bring the AUC back to the range seen without inhibitors, and this should be considered. There are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors, however. If the strong inhibitor is stopped, allow a washout period of about 1 week before the Lapatinib dose is raised back to the indicated dose.

Concomitant strong CYP3A4 inducers: Strong CYP3A4 inducers should also be avoided (e.g., Dexamethasone, Phenytoin, Carbamazepine, Rifampin, Rifabutin, Rifapentin, Phenobarbital, St. John's wort). If a strong CYP3A4 inducer must be given together with Lapatinib, pharmacokinetic studies suggest the Lapatinib dose should be increased gradually, based on how well the patient tolerates it. For the HER2-positive metastatic breast cancer indication, this means going from 1,250 mg/day up to 4,500 mg/day. For the hormone receptor-positive, HER2-positive breast cancer indication, it means going from 1,500 mg/day up to 5,500 mg/day. This dose is predicted to bring the AUC into the range seen without inducers and should be considered. There are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, however. If the strong inducer is stopped, the Lapatinib dose should be brought back down to the indicated dose.

Other toxicities: Lapatinib may be stopped or interrupted when a patient develops NCI CTCAE toxicity of Grade 2 or greater. It can be restarted at the standard dose of 1,250 or 1,500 mg/day once the toxicity improves to Grade 1 or less. If the toxicity comes back, Lapatinib should be restarted at a lower dose, which is 1,000 mg/day with Capecitabine and 1,250 mg/day with Letrozole. Or as directed by the registered physician.

There is no known antidote for a Lapatinib overdose. In clinical trials, the highest oral dose given was 1,800 mg once daily. Taking Lapatinib more often than prescribed could push blood (serum) levels above those seen in the trials and could increase toxicity. So if a dose is missed, don't make it up. Just go back to the next scheduled daily dose.

Cases of overdose have been reported, some with no symptoms and some with symptoms. The doses ranged from 2,500 to 9,000 mg daily and, where it was recorded, the duration varied between 1 and 17 days. The symptoms seen were the usual Lapatinib-associated events and, in some cases, sore scalp, sinus tachycardia (with an otherwise normal ECG), and/or mucosal inflammation.

Lapatinib is not significantly excreted by the kidneys and is highly bound to plasma proteins, so hemodialysis would not be expected to help remove it from the body. Treatment of a Lapatinib overdose should consist of general supportive measures.

Keep Lapatinib below 30°C and in a dry place. Make sure children can't reach it.