PGx Laboratories, a genetic testing lab in Louisville, Ky., is developing a software program that uses genotypic data and physical traits to help physicians adequately dose the anticoagulant warfarin.
The software, which the company expects to roll out within nine to 12 months, is envisioned as a tool that will help doctors navigate the tricky process of warfarin dosing, which currently requires constant careful monitoring due to the narrow therapeutic window of the drug — too low of a dose and it won’t reduce clotting, but too high and the patient faces the risk of hemorrhage.
Variations in the CYP2C9 and VKORC1 genes have been clinically linked to warfarin response, and the US Food and Drug Administration last summer asked drug makers to update the drug’s label to note that patients with these variations should be started at lower initial doses. However, this information has not made it any easier for doctors to determine a safe yet effective maintenance dose.
PGxL is hoping that its software, called PerMIT:Warfarin, or Personalized Medicine Interface Tool, will address this problem by analyzing a patient’s genotypic information — specifically by looking for mutations in the CYP2C9 and VKORC1 genes — with physical characteristics such as age, gender, weight, and height.
“The real challenge for warfarin — whether or not the genotype is known — is the physician being able to determine as quickly as possible what the optimal maintenance dose is for a particular patient,” Kristen Reynolds, vice president of laboratory operations at PGxL, told BioInform.
Time is of the essence, she said, because “during the time while the physician is titrating that dose through what is essentially an educated trial-and-error process, the patient is at an increased risk of having an adverse drug reaction to warfarin, be they bleeding events or thrombotic events.”
Mark Linder, associate director at PGxL and assistant director of chemistry and toxicology at the University of Louisville Hospital, said that the variables that contribute to warfarin dose response are “sufficiently diverse that you can’t come up with a categorical approach to the problem,” in which, for example, everyone with a particular genotype would be prescribed the same dose.
“Really, the only way to reconcile all this information simultaneously was with some sort of informatics tool,” he said.
Linder stressed that the company doesn’t envision the PerMIT:Warfarin as a replacement for the current standard of care, in which a physician administers a relatively low dose of the drug and then monitors the patient’s clotting rate via the INR, or International Normalized Ratio, in order to determine whether to increase the dose.
“We still expect that the INR would be measured, but what the software does is frame it in the right context for that individual so that it’s not misinterpreted.”
“We still expect that the INR would be measured, but what the software does is frame it in the right context for that individual so that it’s not misinterpreted,” he said.
This strategy is in line with the FDA’s recommendation to relabel warfarin, which states that therapy still “be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of [prothrombin time/international normalized ratio] determinations.”
It also gibes with a brochure that the Critical Path Institute and the American Medical Association released this week to its members intended to inform them about using genotypic data when prescribing warfarin. However, the brochure stresses in boldface type that “careful monitoring of INR is still required for optimal dose adjustment” even if they use genotyping to select a starting dose.
“Most of the time you should be able to get a benefit by knowing the genetic makeup of an individual, but that doesn’t mean that that’s all you need to know,” said Ray Woolsey, director of the Critical Path Institute. “You still need to take into account the other factors like gender, body weight, age, and drug interactions,” he said.
“A genetic test will help you better approximate the first dose, but it doesn’t tell you what the first dose is,” Woolsey added. “You can’t cookbook it.”
Computer algorithms “are going to be essential” in guiding dosing “because some of these variants have more weight than others,” he said.
The key to the PGxL software, according to Linder, is that it is intended for ongoing patient care. Unlike a doctor, “it doesn’t forget,” he explained. “If you really put yourself into a practice setting, where you’re trying to manage literally hundreds of patients, you may have done the genotyping at one point in time and know their genotype, but you would really find it difficult to continuously apply that information to your ongoing decisions,” he said.
PerMIT:Warfarin provides “a format for the ongoing utilization of that information,” he said. “So every single time the physician sees that patient and decides to make some dosage-based decision, he can use the tool to put that decision in that person’s genetic or genomic context.”
PGxL is not the only group developing a computational approach to warfarin dosing that uses genetic data. The Barnes-Jewish Hospital at Washington University Medical Center, for example, has developed a free online server called WarfarinDosing.org that estimates therapeutic dose in patients based on clinical factors and CYP2C9 and VKORC1 genotypes.
In addition, the FDA is working with the Harvard Partners Healthcare System to develop a dosing algorithm as part of the 500-patient CROWN, or CReating an Optimal Warfarin Nomogram, trial.
But Linder said that the software PGxL envisions will be more of a decision-support tool than a simple dosing algorithm. He said that the dose-estimation method that underlies the software, which he and his colleagues published in the July 2007 issue of Clinical Chemistry, “only provides you with a target of where you’re likely to be headed. What the overall tool does is give you guidance as you head in that direction.”
In addition, he said that the software was developed as an “operational framework” that can be customized for other drugs, though he declined to disclose what other drugs the company may also be looking at, or its timeframe for doing so.
PGxL believes that the software would predominantly be used for warfarin-naïve patients, which represents around 500,000 to 800,000 individuals per year in the US.
Linder said that the software would also be useful for existing warfarin patients, “particularly those that have demonstrated that they are difficult to stabilize,” but noted that the primary target market would be new patients.