Tuesday, 5 January 2016

The Special One: Cladribine acting in the CNS

Leukaemia in children - what do these studies have to do with the use of Cladribine (2-chlorodeoxyadenosine) in pwMS?  

Well, they revealed over 20 years ago that Cladribine penetrates into the spinal fluid, and in relevant concentrations (about 1/5 - 1/4 of plasma)

Whilst this property is not unique (among drugs used for pwMS) to Cladribine, it is the only drug where its mechanism of action strongly suggests a direct effect within the central nervous system. 

Penetration into the brain may be important for the mechanism by which Cladribine could potentially work not only in those recently diagnosed with MS, but also in people with advanced MS (EDSS>6): Even though at this stage there is generally less significant blood brain barrier leakage and therefore less overt entry of inflammatory cells from the blood stream into the brain, we know that inflammation plays a role throughout the disease, including its advanced stage.  A drug that can attack T and B lymphocytes, and perhaps plasma cells, in the brain of pwMS directly, even without overt blood brain barrier breakdown, may be effective in preserving important functions such as upper limb strength & coordination, cognition and speech.

Monday, 4 January 2016

Shaken or stirred: How would you like your Cladribine?

25 years ago this team of oncologists from the Karolinska University Hospital in Stockholm showed that Cladribine can not only be given as infusion but also as an injection under the skin, or administered as a drink. When taken orally the dose had to be doubled, but the figure below indicates the stunning similarity between all routes of administration in terms of plasma concentration.

Since Merck Serono took over development of oral Cladribine (Movectro), this route of administration cannot be used without infringing their patent.

However remember, only 6 (six) subcutaneous injections (10mg/vial) are required in a year to achieve a dose equivalent to the one successfully used when oral Cladribine was tested in CLARITY and ORACLE MS.

If Movectro gets a license from the EMA, and the annual course of treatment costs say £25,000, would you be prepared to have six injections* instead of generic Cladribine, for example Litak, costing less than £1,000?

This is a serious question.

*No injection site reactions such as those known from beta-interferons. 

Sunday, 3 January 2016

The early days of Cladribine: pharmacokinetics in people with lympho-proliferative disorders

Liliemark J, Juliusson G. Cancer Res 1991;51:5570-2.

The antitumoral effect of 2-chloro-2'-deoxyadenosine (CdA) in the treatment of lymphoproliferative diseases in general and of hairy cell leukemia in particular has recently been demonstrated. Detailed information on the pharmacokinetics of CdA, however, is lacking. The pharmacokinetics of CdA after 2- and 24-h infusions of 0.14 mg/kg was described in 12 patients with lymphoproliferative diseases using a newly developed high-performance liquid chromatography method. The plasma concentration data from individual patients were fitted to a two-compartment model with α- and β-half-lives of 35 ± 12 (mean ± SD) min and 6.7 ± 2.5h, respectively. The volume of distribution was 9.2 ± 5.4 liters/kg. The steady-state concentration of CdA during the 24-h infusion was 22.5 ± 11.1 nM. The areas under the time versus concentration curves were 552 ±258 and 588 ± 185 nM x h, respectively, for the 24- and 2-h infusions. The inter-individual variability of the determinants of the plasma pharmacokinetics of CdA was small (the coefficients of variation were between 0.22 and 0.58). At 6.3 ± 1.5 h after the start of the 2-h infusion, the concentration of CdA was the same as the steady-state concentration during the 24-h infusion. When the mean plasma concentrations of the 12 patients were fitted to a 3-compartment model, the half-lives of the α-, β-, and τ-phases were 8 min, 1 h 6 min, and 6.3 h, respectively. The long terminal half-life of CdA after 2-h infusion supports the use of intermittent infusions.

In a 70kg individual 0.14mg/kg amounts to approximately 10mg, which is the standard vial size of Cladribine across the Globe.

Over 25 years ago this study suggested Cladribine can be administered as short term (2h) rather than long term (24h) infusions without loss of effect.  A significant contribution towards a better understanding of Cladribine's pharmacokinetics to the point at which we are today, where we know it can be administered effectively and conveniently in short courses (infusions, subcutaneous injections, or tablets) in an outpatient setting.