Breath Test Optimizes Carbidopa Dose in Parkinson's Disease

Daniel M. Keller, PhD

June 26, 2012

June 26, 2012 (Prague, Czech Republic) — A breath test in development can help clinicians zero in on the correct dosage of carbidopa for individual Parkinson's disease (PD) patients.

Anil Modak, PhD, of Cambridge Isotopes Laboratories, in Andover, Massachusetts, reported early feasibility data using the test, which uses measures of dopa decarboxylase enzyme activity in PD patients to individualize carbidopa dose.

"What we are trying to do… is give [physicians] a tool by which they can actually personalize the carbidopa medicine, so that the therapy can last much longer and they can give lower doses of L-dopa," Dr. Modak told delegates.

These results were presented here at the 22nd Meeting of the European Neurological Society.

Pilot Study

Combinations of levodopa (L-dopa) and carbidopa are the mainstay of therapy for many patients, and appropriate levels of carbidopa can increase levodopa availability in the central nervous system (CNS) while decreasing its systemic side effects. In all, 70% to 80% of treated PD patients receive L-dopa.

"Oral L-dopa is absorbed into the systemic circulation, crosses the blood-brain barrier [BBB], and is converted to dopamine in the CNS to replace the diminished levels of dopamine in the striatum that are characteristic of the disease," Dr. Modak explained. "L-dopa is given since it crosses the BBB while dopamine does not. However, decarboxylation of L-dopa to dopamine in the peripheral circulation can cause nausea, cardiac arrhythmia, elevated blood pressure, and other adverse effects."

Carbidopa inhibits the activity of dopa decarboxylase in the periphery, making more L-dopa available to the CNS, and decreasing the amount of dopamine in the systemic circulation. However, because of variation in dopa decarboxylase activity between individuals, it is difficult to optimize the carbidopa dose for a given patient.

Dr. Modak indicated that studies have shown that standard carbidopa doses given in combination with L-dopa are insufficient to adequately inhibit peripheral decarboxylation. Therefore, he has developed and holds a patent on a breath test based on a stable, nonradioactive isotope of carbon to measure the activity of an individual's dopa decarboxylase enzyme and arrive at an effective dose of carbidopa.

The breath test depends on labeling L-dopa with 13C at the 1-position and measuring the amount of 13C liberated as exhaled 13CO2 when levodopa is converted to dopamine in the periphery. Measurement is done in less than 2 minutes using a tabletop infrared spectrometer.

Investigators recruited 6 PD patients (age range, 59 to 75 years) at a single Veterans Affairs healthcare facility in the Boston, Massachusetts, area. Five, with PD duration of 3 to 20 years, were already taking L-dopa/carbidopa, while 1 subject, with PD disease duration of 9 months, was treatment-naïve. At each of 5 visits, patients received no carbidopa or a carbidopa dose of 25 mg, 50 mg, 100 mg, or 200 mg in a blinded fashion and 200 mg of 13C-L-dopa as a substrate to measure each subject's dopa decarboxylase activity.

Investigators measured the amount of exhaled 13CO2 before administering the drugs and during the course of 4 hours after medications were given and constructed a dose-response curve for carbidopa to determine the carbidopa dose for optimal inhibition of peripheral L-dopa decarboxylation. They also measured serum levels of homovanillic acid (HVA), a metabolite of dopamine.

While showing curves for 13CO2 in breath and HVA in serum, Dr. Modak said, "The breath curves, the 13CO2 generation, mimics the HVA formation… and as the inhibition increases with increasing doses of carbidopa, the 13CO2 generation decreases, as well as the HVA decreases. So there is a linear correlation between the amount of 13CO2 produced and the HVA in the bloodstream."

Good correlation was noted between areas under the curve for 13CO2 and HVA for 0 to 120 minutes and for 0 to 240 minutes (r 2 = 0.968). "So it's a 2-hour test basically that will enable you to identify which is the proper dose [of carbidopa] for that particular patient," Dr. Modak said. For each patient, the correlations were consistently greater than 0.82 (range, 0.821 to 0.987).

With increasing inhibition of dopa decarboxylase, a rise in the plasma concentration of L-dopa was seen. Plasma L-dopa decreased with increasing exhaled 13CO2.

The greatest inhibition of dopa decarboxylase occurred with a carbidopa dose of 200 mg, but Dr. Modak said that most patients could do well with 25 mg or 50 mg, or in some cases 100 mg.

With an optimal carbidopa dose, "the physicians can then reduce the amount of [L-dopa] given to these patients. What normally happens is they get continuous increase in [L-dopa/carbidopa] as their disease progresses, but what we need to do is to optimize it right from the beginning so that... the therapy lasts a lot longer with minimal doses at minimal toxicity," he suggested.

Interesting Concept

Ilana Schlesinger, MD, head of the Movement Disorders Center in the Department of Neurology at Rambam Medical Center near Haifa, Israel, said that she found the concept of the test interesting and its implementation feasible for a clinic routinely treating PD patients. She was not involved in the study.

"I think that what they're trying to do by adjusting the carbidopa dose in individual patients is noteworthy," Dr. Schlesinger told Medscape Medical News. "The question is, Will it be helpful for the patient in their daily function? We hope that will be true, but that needs to be proven."

Dr. Schlesinger speculated that the test may be particularly useful in treating those patients who cannot increase their doses of levodopa because of nausea. "So right now, we're treating it with other drugs to block the nausea, but maybe this will be a better way of treating the side effects that are peripheral," she said. "I think it's a breakthrough in how we will treat patients if it is found that it is helpful for the patients."

Dr. Modak concurred and said that next steps in research will be to optimize carbidopa dosing based on the breath test and to look at clinical outcomes in terms of the doses of levodopa required and adverse effects.

Dr. Modak holds patents on the breath test. Dr. Schlesinger has disclosed no relevant financial relationships.

22nd Meeting of the European Neurological Society: Abstract O-209. Presented June 10, 2012.