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Tykerb (Lapatinib) - Description and Clinical Pharmacology


TYKERB ® (lapatinib) tablets


Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. It is present as the monohydrate of the ditosylate salt, with chemical name N -(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate. It has the molecular formula C29H26ClFN4O4S (C7H8O3S)2 H2O and a molecular weight of 943.5. Lapatinib ditosylate monohydrate has the following chemical structure:

Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 0.001 mg/mL at 25°C.

Each 250 mg tablet of TYKERB contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base.

The inactive ingredients of TYKERB are: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: FD&C yellow No. 6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide.


Mechanism of Action

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents.



Absorption following oral administration of TYKERB is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hour). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of TYKERB results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours.

At the dose of 1,250 mg daily, steady state geometric mean (95% confidence interval) values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.hr/mL (23.4 to 56 mcg.hr/mL).

Divided daily doses of TYKERB resulted in approximately 2-fold higher exposure at steady state (steady state AUC) compared to the same total dose administered once daily.

Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a low fat (5% fat-500 calories) or with a high fat (50% fat-1,000 calories) meal, respectively.


Lapatinib is highly bound (>99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer resistance protein (BCRP, ABCG2) and P-glycoprotein (Pgp, ABCB1). Lapatinib has also been shown in vitro to inhibit these efflux transporters, as well as the hepatic uptake transporter OATP 1B1, at clinically relevant concentrations.


Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.


At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours.

Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3 to 67%) of an oral dose.

Effects of Age, Gender, or Race

Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed.

QT Prolongation

The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open-label dose escalation study in advanced cancer patients. Eighty-one patients received daily doses of lapatinib ranging from 175 mg/day to 1,800 mg/day. Serial ECGs were collected on Day 1 and Day 14 to evaluate the effect of lapatinib on QT intervals. Thirteen of the 81 subjects were found to have either QTcF (corrected QT by the Friedericia method) >480 msec or an increase in QTcF >60 msec by automated machine-read evaluation of ECG. Analysis of the data suggested a relationship between lapatinib concentration and the QTc interval.


Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies with lapatinib are ongoing.

Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays.

There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human clinical exposure based on AUC, respectively).


The efficacy and safety of TYKERB in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) over-expressing (IHC 3+ or IHC 2+ confirmed by FISH), locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes, and trastuzumab.

Patients were randomized to receive either TYKERB 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m2/day on Days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m2/day on Days 1-14 every 21 days. The endpoint was time to progression (TTP). TTP was defined as time from randomization to tumor progression or death related to breast cancer. Based on the results of a pre-specified interim analysis, further enrollment was discontinued. Three hundred and ninety-nine (399) patients were enrolled in this study. The median age was 53 years and 14% were older than 65 years. Ninety-one percent (91%) were Caucasian. Ninety-seven percent (97%) had stage IV breast cancer, 48% were estrogen receptor+ (ER+) or progesterone receptor+ (PR+), and 95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation. Approximately 95% of patients had prior treatment with anthracyclines, taxanes, and trastuzumab.

Efficacy analyses four months after the interim analysis are presented in Table 3, and Figure 1, and Figure 2.

Table 3. Efficacy Results

Independent Assessment*

Investigator Assessment

TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m 2/day

Capecitabine 2,500 mg/m 2/day

TYKERB 1,250 mg/day + Capecitabine 2,000 mg/m 2/day

Capecitabine 2,500 mg/m 2/day

(N = 198)

(N = 201)

(N = 198)

(N = 201)

Number of TTP events





Median TTP, weeks





(25th, 75th, Percentile), weeks

(17.4, 49.4)

(9.1, 36.9)

(12.0, 44.0)

(6.9, 35.7)

Hazard Ratio



(95% CI)

(0.43, 0.77)

(0.56, 0.92)

p value



Response Rate (%)





(95% CI)

(18.0, 30.3)

(9.5, 19.5)

(25.4, 38.8)

(12.4, 23.4)

TTP = Time to progression.

* The time from last tumor assessment to the data cut-off date was >100 days in approximately 30% of patients in the independent assessment. The pre-specified assessment interval was 42 or 84 days.

Figure 1. Kaplan-Meier Estimates for Independent Review Panel-evaluated Time to Progression

Figure 1. Kaplan-Meier Estimates for Independent Review Panel-evaluated Time to Progression

Figure 2. Kaplan-Meier Estimates for Investigator Assessment Time to Progression

Figure 2. Kaplan-Meier Estimates for Investigator Assessment Time to Progression

At the time of updated analysis, 30% of patients had died and the data for survival analysis are not mature. Fifty-five patients (28%) in the TYKERB plus capecitabine group and 64 subjects (32%) in the capecitabine group had died.

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