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Tham et al. (2008), A Pharmacodynamic Model for the Time Course of Tumour Shrinkage by Gemcitabine + Carboplatin in Non-Small Cell Lung Cancer Patients

January 2010, model of the month by Vijayalakshmi Chelliah
Original model: BIOMD0000000234

The drug development process is greatly benefited by the advancement in the PharmacoKinetic (PK) / PharmacoDynamic (PD) ([1], research and modeling techniques. PharmacoKinetics (simply refered as, what the body does to a drug), describe the relationships between the dosage and the profile of drug concentration in the body fluids over time. PharmacoDynamics (simply refered as, what a drug does to the body), describes the relationship between the drug effect on the body over time. A range of factor, including age, body weight, sex, renal function, liver function, genetic factor, disease status, drug - interaction, absorbtion, distribution and clearance, and various other factors can influence the pharmacokinetic of a drug, and consequently the pharmacodynamics (i.e. the patients response to the drug therapy). Therefore, drug dosage adjustments are often required to ensure that the patients achieves an adequate dose without risk in toxicity, and this is where the PK/PD modeling studies plays a potential role.

The model by Tham et al., 2008 ([2], BIOMD0000000234), describes the PD model of Gemcitabine in combination with Carboplatin for the treatment of Non-small cell lung cancer, and study the drug effect on the tumour size in relation to the dosage.

Gemcitabine (Figure 1, figure taken from ChEBI), a synthetic pyrimidine nucleoside antimetabolite anticancer agent with complex metabolic pathways, is a group of chemotherapy drug. Initially, cytidine deaminase deactivates the parent compound - an inactive prodrug and its major inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) is formed. Extracellularly, a small fraction is also catabolized via a pathway mediated by pyrimidine nucleoside phosphorylase. The remaining gemcitabine and dFdU are then transported into the cell and activated intracellularly through progressive phosphorylations by deoxycytidine kinase. The metabolites produced through this process of phosphorylation are the monophosphate, diphosphate, and triphosphate (dFdCTP) forms of gemcitabine, the latter being its active metabolite.

Chemical Structure of the Chemotherapy Drugs Gemcitabine and Carboplatin

Figure 1: Chemical Structure of the Chemotherapy Drugs A) Gemcitabine and B) Carboplatin. Figures taken from CHEBI:175901 and CHEBI:31355.

Non-small cell lung cancer

Figure 2: Non-small cell lung cancer. Figure taken from here.

It arrests cell cycle in two ways. 1) As with fluorouracil and other analogues of pyrimidines, the triphosphate analogue of gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumor growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis. 2) Another target of gemcitabine is the enzyme ribonucleotide reductase (RNR). The diphosphate analogue binds to RNR active site and inactivates the enzyme irreversibly. Once RNR is inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair, and cell apoptosis is induced.[3]

Gemcitabine is widely used in the treatment of cancers and has shown activity against a variety of solid tumours, including pancreatic, breast, bladder, ovarion and non-small cell lung cancer. Notable effect of the treatment is observed when Gemcitabine is used in combination with Carboplatin (Figure 1, taken from CHEBI:31355) or its parent compound Cisplatin, another chemotherapy drug which has an atom of the metal platinum at the centre. Carboplatin forms DNA cross links via the platinum atom, which damage the cancer cells. Carboplatin is most commonly used to treat ovarian and lung cancer. GemCarbo (combination of Gemcitabine and Carboplatin) is most often used to treat non-small cell lung cancer and bladder cancer.

This paper investigates a longitudinal tumour response model to describe and predict the response of the primary lesion in non-small cell lung cancer (Figure 2, taken from here) to gemcitabine (with carboplatin) chemotherapy.

A total of 202 tumour size measurements from 56 patients were used to establish the pharmacodynamic model for tumour response. Gemcitabine was infused at either a fixed dose rate of 750mg/m2 over 75 mins or 1000mg/m2 over 30 mins on days 1 and 8 every 3 week in stage IIIB or IV non-small cell lung cancer patients. Carboplatin dose was administered as a 1hour infusion just before gemcitabine on day 1 of every cycle to patients. The pharmacokinetic exposure variables are the Gemcitabine dose and the AUCs (concentration-time curve) corresponding to each dose given, over the entire duration of treatment. Serial measurements of the largest dimension of the primary tumour were done on radiological images using electronic calipers at baseline after cycles 2, 4 and 6 and bimonthly thereafter for at least 4 months after tratment. The tumour size measurement (sum of the longest unidimensional measurement) were used as the drug response measure for the pharmacodynamic model. Figure 3 shows a comparison of drug dose, effective exposure and tumour size change over time. A Gemcitabine amount in the body of 10,600mg is required to achieve a 50% reduction in tumour growth rate (baseline tumour size being 6.66cm). The reduce in tumour size indicate the rate of cancerous cells killed due to the effect of drug.

The pharmacodynamic model deducing the potency and time course of the anticancer agent in shrinking the primary tumours can have potential role to decide dosage and treatment duration. As these examinations can be routinely done during early phase of clinical trials, this could give further insights in the drug development process and also gives improved understanding of the clinical actions of drugs that are already marketed.

A comparison of drug dose, effective exposure and tumour size change over time.

Figure 3: A comparison of drug dose (blue), effective exposure (red) and tumour size (green) change over time. Simulation result taken from BIOMD0000000234.

Bibliographic References

  1. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Pharmacokinetics, pharmacodynamics and drug disposition. In: Davis KL, Charney D, Coyle JL, Nemeroff C, editors. Neuropsychopharmacology: the fifth generation of progress. Baltimore (MD): Lippincott, Williams and Wilkins; p. 507-24. 2002. [PDF]
  2. Tham LS, Wang L, Soo RA, Lee SC, Lee HS, Yong WP, Goh BC, Holford NH. A pharmacodynamic model for the time course of tumor shrinkage by gemcitabine + carboplatin in non-small cell lung cancer patients. Clin. Cancer Res. , 14(13):4213-8, 2008. [CiteXplore]
  3. Cerqueira NM, Fernandes PA, Ramos MJ. Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry. , 13(30):8507-15, 2007 [CiteXplore]