Lapatinib
When ATH:
L01XE07
Pharmacological action
The antitumor agent, reversible, selective inhibitor of the intracellular tyrosine kinase. Associated with the epidermal growth factor receptor (epidermal growth factor receptor – EGFR/ErbB1 и human epidermal growth factor receptor – HER2 /neu/ЕrbВ2 ). It differs from other tyrosine kinase inhibitors bystroobratimyh slower dissociation with ErbB1- and ErbV2 receptors (period of dissociation 50% ligand from the ligand-receptor complex is approximately 300 m).
In addition to its own in vitro activity has been demonstrated additive activity of lapatinib and 5-fluorouracil (the active metabolite of capecitabine) when used in combination for four tumor cell lines. The inhibitory effect was evaluated for trastuzumab-treated cells. Lapatinib demonstrated significant activity on tumor cell lines immortalized in media, containing trastuzumab, that shows no cross-resistance between the two ligands HER2 / neu / ErbB2 .
According to the research lapatinib is an active drug, when administered as monotherapy in patients with metastatic breast cancer. The results showed, that the combined use of lapatinib with capecitabine for the treatment of patients with erbB2-positive advanced breast cancer increases the time to progression, and significantly, and significantly reduces the risk of disease progression.
It was identified a trend towards improved survival, and reduced the risk of death.
Pharmacokinetics
Absorption after oral administration is incomplete and variable. The coefficient of variability of AUC is from about 50 to 100%. Defined in the systemic circulation at a mean 0.25 no (range 0-1.5 no). Cmax is reached after about 4 h after administration of lapatinib.
Cssmax in equilibrium with the daily intake of a dose 1250 mg averages 2.43 (1.57-3.77) ug / ml, AUC – 36.2 (23.4-56) g × h / ml.
The bioavailability of lapatinib is dependent on food intake. Systemic exposure of lapatinib is increased when taking the drug at the same time food. AUC increases 3 and 4 times, Cmax about 2.5 and 3 times higher when taken with food low or high fat, respectively.
Lapatinib has a high degree of binding (more than 99%) albumin and alpha-1-acid glycoprotein plasma.
Lapatinib undergoes extensive metabolism, mainly via CYP3A4 and CYP3A5, to a lesser extent CYP2C19 and CYP2C8 to form various oxygenated metabolites.
In vitro lapatinib at clinically relevant concentrations inhibits CYP2C8 CYP3Ai. Lapatinib inhibits slightly following microsomal liver enzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6.
T1 / 2 increased dose-dependently when receiving single doses. The equilibrium state is achieved after 6-7 day reception, T1 / 2 in the equilibrium state is 24 no.
The main conclusions intestine – average 27% in unchanged form, less 2% the dose is excreted by the kidneys unchanged and as metabolites.
It is unlikely the effect of renal impairment on the pharmacokinetics of lapatinib.
The pharmacokinetics of lapatinib has been studied at moderate (7-9 points on the Child-Pugh classification, n=8) and heavy (>9 points on the Child-Pugh classification, n=4) hepatic dysfunction. AUC lapatinib after a single dose 100 mg incremented by 56% and 85% respectively.
Testimony
Distribution and / or metastatic breast cancers overexpressing ErbB2 (HER2 )-receptors, as part of combination therapy with capecitabine, patients, previously treated with, which included trastuzumab.
Dosage regimen
Lapatinib is used in combination with capecitabine.
Recommended in the dose of lapatinib 1250 mg 1 time /, daily. Lapatinib is taken as 1 hours before or after 1 h postprandial.
Missed dose of lapatinib is not replenished, ie. take the missed dose, reducing intervals between doses, should not.
At the same time apply a special scheme for capecitabine.
Treatment of lapatinib should be discontinued if symptoms decrease left ventricular ejection fraction to 3 degree or more (classification of adverse events of the National Cancer Institute), or in the case of reduction below the admissible norm. Lapatinib treatment can be resumed not earlier than 2 weeks at a lower dose (1000 mg /) and only if the level of left ventricular ejection fraction is within the acceptable normal limits.
Treatment of lapatinib should be discontinued in the event of pulmonary symptoms indicative of interstitial lung development process / pneumonitis 3 degree or more (classification of adverse events of the National Cancer Institute).
The decision to terminate the application or change the dose of lapatinib can be accepted, when the level of developing toxic effects matches 2 degree and a classification of adverse events of the National Cancer Institute. By reducing the level of toxic effects decreased to 1 degrees and less treatment may be resumed at a dose 1250 mg / In case of repeated occurrence of toxic effects of lapatinib dose should be reduced to 1000 mg /
Side effect
Monotherapy lapatinibom
From the digestive system: Often – anorexia, diarrhea (which can lead to dehydration), nausea, vomiting; sometimes – giperʙiliruʙinemija, increased ALT, IS, Alkaline phosphatase.
Cardio-vascular system: often – decrease in left ventricular ejection fraction (90% – symptomatic). It resolves spontaneously in 60% patients after drug withdrawal. Symptomatic decrease in left ventricular ejection fraction was observed in 0.1% patients (dyspnoea, heart failure, palpitations).
The respiratory system: sometimes – interstitial pulmonary process / pneumonitis.
Dermatological reactions: Often – rash (including acne).
From the body as a whole: Often – weakness.
Lapatinib in combination with capecitabine
From the digestive system: Often – dyspepsia.
Dermatological reactions: Often – xerosis.
Occurred with the same frequency in the lapatinib group + capecitabine and capecitabine gruppe
From the digestive system: Often – stomatitis, constipation, abdominal pain, giperʙiliruʙinemija.
Dermatological reactions: Often – palmar-plantar eritrodizesteziya.
From the body as a whole: Often – mukozit.
On the part of the musculoskeletal system: Often – pain in the back and limbs.
CNS: Often – insomnia; often – headache.
Contraindications
Pregnancy, lactation (breast-feeding), Hypersensitivity to lapatinib.
Cautions
Treatment of lapatinib should be carried out only under the supervision of a specialist, with experience of chemotherapy.
Caution should be used when conditions, which can lead to left ventricular failure, hepatic dysfunction moderate or severe (7 and more points on the Child-Pugh).
Consideration should be given information on contraindications and safety of capecitabine in the combined use with lapatinib.
Before treatment is necessary to assess the level of left ventricular ejection fraction. During treatment should monitor the level of left ventricular ejection fraction, to prevent the reduction of this index below the permissible values. Treatment of lapatinib should be discontinued in case of decrease in ejection fraction to 3 degree or more, or in the case of reduction below the admissible norm. Lapatinib treatment can be resumed not earlier than 2 weeks at a lower dose (1000 mg / only if the level of left ventricular ejection fraction is within the acceptable normal limits). A permanent decline in left ventricular ejection fraction for 9 weeks of treatment, usually, It limits the duration of therapy.
During treatment, patients should be monitored for pulmonary symptoms detection, indicating the development of interstitial pulmonary process / pneumonitis.
At the first sign of diarrhea recommended the appointment of antidiarrheal drugs. If severe diarrhea may require the appointment of electrolytes and fluids to prevent dehydration (PO / in), receiving lapatinib suspension or revocation.
Before treatment, then monthly, or by clinical indications should monitor liver function tests (Activity of transaminases, Alkaline phosphatase, bilirubin). In severe liver dysfunction should discontinue treatment lapatinib, re-treatment is not carried out. There are cases of hepatotoxicity in the appointment of tyrosine kinase inhibitors. In patients with impaired liver function is not enough data to generate specific recommendations for the correction of dosing regimen.
Patients with impaired renal function does not require correction dosing regimen.
Experience with the drug in children is not
There was no difference in the effectiveness of, tolerability and safety of lapatinib depending on the age (elderly patients).
Effects on ability to drive vehicles and management mechanisms
The mechanism of action of lapatinib suggest no effect on the ability to concentrate. Nonetheless, It should take into account the overall clinical condition of the patient and the possible development of adverse events when assessing the ability to drive a car and operate machinery, requiring quick response.
Drug Interactions
CYP3A inducers or inhibitors can affect the pharmacokinetics of lapatinib. With simultaneous use of lapatinib and known inhibitors of CYP3A (eg, ketoconazole, itraconazole, grapefruit juice) you must be careful and closely monitor the patient's clinical condition and possible adverse reactions. If necessary, the patient co-administration of strong CYP3A4 inhibitor necessary to reduce the dose of lapatinib 500 mg /, calculated as, to adjust the lapatinib AUC to the value, appropriate use of lapatinib without inhibitors. But, no clinical data lapatinib at a dose adjustment for patients, receiving a potent inhibitor of CYP3A4. After canceling a strong inhibitor, Only after removing it from the body, after about 1 week should again increase the dose to the recommended lapatinib.
With simultaneous use of lapatinib and known inducers of CYP3A4 (eg, rifampicin, Carbamazepine, phenytoin) and you must be careful and closely monitor the patient's clinical condition and possible adverse reactions.
If necessary, the patient co-administration of strong CYP3A4 inducer dose of lapatinib should be selected based on tolerance, gradually increasing it with 1250 mg / up 4500 mg / This dose is calculated as, to adjust the lapatinib AUC to the value, appropriate use of lapatinib without inductors. However, no clinical data in patients lapatinib, receiving strong CYP3A4 inducer. After the abolition of the strong inducer, Only after about 2 week should again be reduced to the recommended dose of lapatinib.
Lapatinib inhibits the in vitro CYP3A4 and CYP2C8 at clinically relevant concentrations. Care should be taken while the appointment of lapatinib and drugs with a narrow therapeutic range, are substrates of these enzymes. Lapatinib is a substrate for the transport proteins P glycoprotein and BCRP. Inhibitors and inducers of these proteins may alter the action and / or distribution of lapatinib.
It is not excluded, lapatinib that can affect the pharmacokinetics of the glycoprotein substrates P (eg, digoksina), BCRP (eg, Topotecan) and OATR1V1 (eg, rosuvastatin).
