HORSHAM, Penn--Sparta Pharmaceuticals, Inc. has completed a phase I
clinical trial of Spartaject busulfan, an injectable form of
busulfan, an agent that is poorly water soluble and currently
available only in tablet form.
The Spartaject technology accommodates poorly water soluble and water
insoluble compounds by encapsulating fine particles of the drug with
a phospholipid layer, thereby permitting the creation of a suspension
of the drug, rather than a solution, and avoiding the use of
potentially toxic solubilizing agents (see
figure).
The phase I trial of Spartaject busulfan was conducted at Johns
Hopkins Oncol-ogy Center and Duke University. Louise Grochow, MD, of
Johns Hopkins, led the study, and, together with Lori Hollis, PharmD,
presented interim data from the trial at the American Association for
Cancer Research 1998 meeting.
Patients in the study received oral and intravenous busulfan for
myeloablation prior to bone marrow transplantation for the treatment
of various types of cancer. Safety and bioavailability at low and
high doses were assessed. Results showed that busulfan blood levels
were less variable after IV busulfan than after oral busulfan.
The variability seen after oral dosing may contribute to toxicity or
problems with bone marrow engraftment, the researchers said.
Furthermore, oral dosing requires patients to take as many as 100
tablets a day for 4 days.
In her presentation, Dr. Grochow said that "parenteral
administration of busulfan may permit more consistent drug exposure,
simplify drug administration and therapeutic monitoring, and further
reduce the incidence of venoocclusive disease."
In an interview, Martin Rose, MD, JD, Spartas vice president
for clinical and regulatory affairs, said that the FDA has accepted
the companys plans to begin pivotal phase II/III clinical
trials of Spartaject busulfan as preparative therapy for adult cancer
patients treated with bone marrow transplantation. The agent has also
received orphan drug designation for that indication.
Two other phase I trials of the agent are in progress, Dr. Rose said.
At Duke University Medical Center, in a study led by Henry Friedman,
MD, Spartaject busulfan is being injected intrathecally for the
treatment of neoplastic meningitis in adults and children. At St.
Jude Childrens Research Hospital, Spartaject busulfan will be
given to pediatric patients being prepared for bone marrow
transplantation. Principal investigator for this study is John
Rodman, PharmD.
Dr. Rose also noted that Sparta has licensed its Spartaject drug
delivery technology to Schering-Plough for use with the companys
anticancer agent Temodal (temozolomide). Schering-Plough submitted a
new drug application (NDA) to the FDA in August 1998 for the use of
orally administered Temodal to treat recurrent malignant gliomas.
In the interview, Dr. Rose pointed out a number of differences
between Sparta-ject technology and liposomal techniques for creating
injectable agents. He said that the Spartaject technology can be
applied to agents that are completely water insoluble, whereas
liposomes are used primarily for drugs that are at least slightly
water soluble.
The drug:lipid ratio with Spartaject is approximately 1:1, compared
with approximately 1:20 with some liposomes, "a lot more lipid
and a lot less drug than with Spartaject," he said. "Our
particle size is in the 2 to 5 micron range, less than the size of a
red blood cell," he added, "and our particles are
distributed evenly in the circulation, whereas liposomes are taken up
preferentially by certain tissues such as the liver, spleen, and
reticuloendothelial system."
He noted that Spartaject busulfan is a stable product with a
shelf-life of at least 1 year, and that reconstitution of the drug is
a simple process. "You just add water for injection and shake it
up," he said, "whereas with liposomes it can be more complicated."
Dr. Rose said that, in addition to allowing IV delivery of existing
oral drugs, the technology can potentially be used to improve
existing injectable drugs by reducing formulation toxicities, and
permit the renewed development of anti-cancer and antiviral agents
whose development may have been halted because of formulation
difficulties attributable to poor solubility.
