Solithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intent-to-treat (ITT) (84.6% for solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for solithromycin; 5.9% for levofloxacin), and vomiting (0% for solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.)
Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.
Pyronaridine; Plasmodium falciparum; Plasmodium vivax; Review; Artemisinin containing compound; Anti-malarial therapy
With the emergence of Plasmodium falciparum infections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potent in vitro activity against the NF54 strain of P. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In an in vivo model of P. berghei infection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promising in vitro and in vivo data support further investigations into the development of solithromycin as an antimalarial agent.
The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food.
Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates.
A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction.
A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.
The human tumour suppressor gene PTEN located at 10q23 is mutated in a variety of tumour types particularly metastatic cases and in the germline of some individuals with Cowdens cancer predisposition syndrome. We have assessed the status of PTEN and associated pathways in cell lines derived from 19 squamous cell carcinomas of the head and neck. Loss of heterozygosity is evident at, or close to the PTEN gene in 5 cases, however there were no mutations in the remaining alleles. Furthermore by Western analysis PTEN protein levels are normal in all of these SCC-HN tumours and cell lines. To assess the possibility that PTEN may be inactivated by another mechanism, we characterized lipid phosphatase levels and from a specific PIP3 biochemical assay it is clear that PTEN is functionally active in all 19 human SCCs. Our data strongly suggest the possibility that a tumour suppressor gene associated with development of SCC-HN, other than PTEN, is located in this chromosomal region. This gene does not appear to be MXI-1, which has been implicated in some other human tumour types. PTEN is an important negative regulator of PI3Kinase, of which subunit alpha is frequently amplified in SCC-HN. To examine the possibility that PI3K is upregulated by amplification in this tumour set we assessed the phosphorylation status of Akt, a downstream target of PI3K. In all cases there is no detectable increase in Akt phosphorylation. Therefore there is no detectable defect in the PI3K pathway in SCC-HN suggesting that the reason for 3q26.3 over-representation may be due to genes other than PI3K110α. © 2001 Cancer Research Campaign http://www.bjcancer.com
PTEN; LOH; carcinoma; P13K
To evaluate the potential for an interaction between clarithromycin and loratadine, healthy male volunteers (n = 24) received each of the following regimens according to a randomized crossover design: 500 mg of clarithromycin orally every 12 h (q12h) for 10 days, 10 mg of loratadine orally q24h for 10 days, and the combination of clarithromycin and loratadine. A washout interval of 14 days separated regimens. The addition of loratadine did not statistically significantly affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxy-clarithromycin. However, the addition of clarithromycin statistically significantly altered the steady-state maximum observed plasma concentration and the area under the plasma concentration-time curve over a dosing interval for loratadine (+36 and +76%, respectively) and for descarboethoxyloratadine (DCL), the active metabolite of loratadine (+69 and +49%, respectively). Clarithromycin probably inhibits the oxidative metabolism of loratadine and DCL by the cytochrome P-450 3A subfamily. Electrocardiograms (n = 12) were obtained over 24-h periods at baseline and steady state (day 10). The mean maximum QTc interval and area under the QTc interval-time curve on day 10 were modestly increased (<3%) from baseline for all three regimens, but no QTc interval exceeded 439 ms for any subject. Elevated steady-state concentrations of loratadine and DCL do not appear to be associated with adverse cardiovascular effects related to prolongation of the QTc interval. Loratadine and clarithromycin were well tolerated, alone and in combination.
The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
In this study, autoantibodies to RNA polymerase II from sera of patients with systemic sclerosis have been identified and characterized. These antibodies immunoprecipitated polypeptides of 220 kD (IIA) and 145 kD (IIC), the two largest subunits of RNA polymerase II, and bound both subunits in immunoblots. These polypeptides were immunoprecipitated by the anti-RNA polymerase II monoclonal antibody 8WG16, which recognizes the carboxyl-terminal domain of the 220-kD subunit, and their identity to the proteins bound by human sera was confirmed in immunodepletion studies. Sera with anti-RNA polymerase II antibodies also immunoprecipitated proteins that were consistent with components of RNA polymerases I and III. In vitro transcription experiments showed that the human antibodies were an effective inhibitor of RNA polymerase II activity. In indirect immunofluorescence studies, anti-RNA polymerase II autoantibodies stained the nucleoplasm, as expected from the known location of RNA polymerase II, and colocalized with the anti-RNA polymerase II monoclonal antibody. The human sera also stained the nucleolus, the location of RNA polymerase I. From a clinical perspective, these antibodies were found in 13 of 278 patients with systemic sclerosis, including 10 with diffuse and three with limited cutaneous disease, but were not detected in sera from patients with other connective tissue diseases and from normal controls. We conclude that anti-RNA polymerase II antibodies are specific to patients with systemic sclerosis, and that they are apparently associated with antibodies to RNA polymerases I and III. These autoantibodies may be useful diagnostically and as a probe for further studies of the biological function of RNA polymerases.
The single- and multiple-dose pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite in infants and children were studied after oral administration under fasting and nonfasting conditions. Drug absorption appeared to be rapid following a brief delay in its onset; the mean peak concentrations in plasma (Cmax) for clarithromycin were reached within about 3 h under both conditions. The mean Cmax for the parent drug were 3.59 and 4.58 micrograms/ml in single-dose fasting and nonfasting patients, and the respective Cmax for the metabolite were 1.19 and 1.26 micrograms/ml. Data indicate good absorption and no significant effects by food. There was no unusual accumulation in the area under the concentration-time curve and Cmax in the multiple-dose group.
The pharmacokinetics of temafloxacin were investigated following oral administration of single 400-mg doses to 6 normal subjects and 18 subjects with various degrees of impaired renal function. Renal impairment did not significantly affect the peak concentration, time to peak concentration, or the nonrenal clearance of temafloxacin. Both renal clearance (CLR) and total apparent clearance (CLT/F, where F represents the fraction of dose absorbed) of temafloxacin were highly correlated with creatinine clearance (CLCR). The regression equations were as follows: CLR = 0.85.CLCR, with R2 = 0.907, and CLT/F = 56.0 + 0.92.CLCR, with R2 = 0.656. The half-life (mean +/- standard deviation) increased from 10.6 +/- 2.4 h in the normal volunteers to 24.6 +/- 7.3 h in the subjects with a CLCR of less than 10 ml/min; the respective CLT/F decreased from 169 +/- 58 to 70 +/- 27 ml/min. Compared with the CLT/F in the subjects with normal renal function, CLT/F was reduced 60% in subjects with a CLCR of less than 40 ml/min, indicating that the dosage should be reduced by at least one-half for patients with comparable impairment. For the subjects on chronic hemodialysis, most of the variability in the nonrenal clearance and the terminal-phase rate constant of temafloxacin was associated with the quantity of calcium carbonate and related medication taken for the treatment of hyperphosphatemia. Supplemental dosage is not required for patients undergoing hemodialysis, since the distribution of temafloxacin in tissue is extensive and the recoveries from 4-h dialysis sessions accounted for less than 10% of the drug present at the start of the dialysis.
Anti-Ro autoantibodies, found in sera of patients with systemic lupus erythematosus, Sjogren's syndrome, and related diseases, target the Ro ribonucleoprotein particles (RNPs). Although the polypeptide and RNA components of the Ro RNPs have been characterized, much less is known about the native structure of these particles. We have now characterized by biochemical techniques intact Ro ribonucleoprotein particles from cultured HeLa cells. These particles segregated in three discrete subpopulations with characteristic physicochemical properties: one containing hY5 RNA (RohY5 particles), one containing only hY4 RNA (RohY4 particles) and one with hY1, hY3, and hY4 RNAs (RohY1-hY4 particles). The RohY5 particles were purified free of contaminating ribonucleoproteins; both the La and the 60-kD Ro polypeptides were stable components of this portion of the Ro RNPs. The La RNPs co-purified with the RohY4 particles and contaminated the RohY1-hY4 RNPs. The stable association between the La and the 60-kD Ro polypeptides provides a potential macromolecular target for the linked set of anti-Ro and anti-La antibodies, and suggests a possible functional association of these polypeptides.
Anti-Ro autoantibodies found in sera from patients with systemic lupus erythematosus and related diseases precipitate four RNAs (hY1-hY5) from human cell extracts. We identified two patient sera that selectively immunoprecipitated from such extracts the Ro particle containing the hY5 RNA (RohY5 particle). Using cell fractions either enriched in or depleted of RohY5 particles, we have shown that these sera contain autoantibodies that target an antigenic determinant on the 60-kD Ro polypeptide that is expressed only on RohY5 particles and is absent on the Ro particles containing the hY1-hY4 RNAs (RohY1-hY4 particles). In a competitive inhibition assay using a cell fraction enriched in RohY1-hY4 particles but depleted of RohY5 particles, four of six control anti-Ro sera were also shown to contain antibodies reactive with the epitope specific for the RohY5 particle. Thus anti-RohY5 antibodies frequently occur in tandem with anti-Ro antibodies, but are not detected unless inhibition assays are performed. Finally, anti-RohY5 specific sera do not immunoprecipitate any Ro particles from various nonhuman cell lines. In contrast to other autoantibodies in systemic lupus and related diseases that bind conserved regions on conserved polypeptides, this observation suggests that a portion of the anti-Ro response targets a nonconserved epitope on a conserved autoantigen.
Antigen detection methods may facilitate diagnosis of Giardia lamblia in stool specimens. As determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and immunoblotting, G. lamblia cysts and trophozoites share several antigens, especially in the 65-kilodalton and 30- to 34-kilodalton regions. By using blind methods, we compared results obtained by counterimmunoelectrophoresis using cyst-immune rabbit serum and by enzyme-linked immunosorbent assay (ELISA) using trophozoite-immune rabbit serum with results obtained by microscopic examination of a preserved, concentrated, and permanently stained stool specimen. Results were similar when these three methods were used to examine 118 stool specimens from clinical microbiology laboratories (53 specimens with G. lamblia) and specimens from 239 day-care-center toddlers (39 specimens with G. lamblia). Compared with microscopy, we found, for counterimmunoelectrophoresis and ELISA, respectively: sensitivity, 88 versus 94%; specificity, 97 versus 95%; positive predictive value, 86 versus 76%; negative predictive value, 98 versus 97%; and concordance, 89%. The false-positive rate by ELISA was 24% (10 of 42) in day-care-center toddlers but only 3% (1 of 32) in healthy adults (P less than 0.04) as corroborated by microscopy. This discrepancy suggests that the ELISA may be more sensitive than microscopy, which is considered the reference standard, and that results may be dependent, in part, on the epidemiology of the infection in the study subjects.
We identified eight patients whose sera contained autoantibodies to the U2 small nuclear ribonucleoprotein (snRNP), an RNA protein particle involved in the splicing of newly transcribed messenger RNA. Each of these patients had an overlap syndrome that included features of either systemic lupus erythematosus (SLE), scleroderma, and/or polymyositis. We then used these sera to characterize the autoantigenic polypeptides of the U1 and U2 snRNP particles. In immunoblots, all sera contained antibodies to the B" polypeptide of the U2 snRNP. A subset of these sera that more effectively immunoprecipitated the native U2 particle contained an additional antibody system that recognized the A' polypeptide of this snRNP. Antibodies eluted from the B" protein bound the A polypeptide of the U1 snRNP and vice versa. Moreover, antibodies to the B" polypeptide were accompanied by antibodies to the 68K and C polypeptides of the U1 snRNP. Finally, the A' and B" polypeptides remained physically associated after the U2 particle was cleaved with RNase. Thus these sera contain multiple autoantibody systems that, at one level, target two physically associated antigenic polypeptides of the U2 particle and, at another, target two snRNP particles which are associated during the splicing of premessenger RNA. These linked autoantibody sets provide further evidence that intact macromolecular structures are targeted by the immune response in SLE and related diseases.
A 46-year-old woman with a history of breast carcinoma and no known metastatic disease presented with iridocyclitis and secondary glaucoma. Intraocular inflammation and pressure elevation persisted despite standard medical therapy, and paracentesis was performed. Cytological examination of the aspirate revealed adenocarcinoma. Subsequent studies disclosed no evidence of extraocular metastasis. Two courses of radiation therapy to the involved eye resulted in a dramatic reduction in intraocular inflammation and allowed temporary control of the intraocular pressure. Ultimately, however, progressive glaucoma necessitated enucleation. This case confirms previous statements that iridocyclitis may be the initial clinical manifestation of metastatic malignancy. In addition, this report emphasises the importance of paracentesis in the diagnostic evaluation of selected cases of anterior uveitis of unknown aetiology.
Using immunoblots, we identified proteins of Borrelia burgdorferi bound by IgM and IgG antibodies during Lyme disease. In 12 patients with early disease alone, both the IgM and IgG responses were restricted primarily to a 41-kD antigen. This limited response disappeared within several months. In contrast, among six patients with prolonged illness, the IgM response to the 41-kD protein sometimes persisted for months to years, and late in the illness during arthritis, a new IgM response sometimes developed to a 34-kD component of the organism. The IgG response in these patients appeared in a characteristic sequential pattern over months to years to as many as 11 spirochetal antigens. The appearance of a new IgM response and the expansion of the IgG response late in the illness, and the lack of such responses in patients with early disease alone, suggest that B. burgdorferi remains alive throughout the illness.
We determined the antibody response against the Ixodes dammini spirochete in Lyme disease patients by indirect immunofluorescence and an enzyme-linked immunosorbent assay (ELISA). The specific IgM response became maximal three to six weeks after disease onset, and then declined, although titers sometimes remained elevated during later disease. Specific IgM levels correlated directly with total serum IgM. The specific IgG response, often delayed initially, was nearly always present during neuritis and arthritis, and frequently remained elevated after months of remission. Although results obtained by indirect immunofluorescence and the ELISA were similar, the ELISA was more sensitive and specific. Cross-reactive antibodies from patients with other spirochetal infections were blocked by absorption of sera with Borrelia hermsii, but titers of Lyme disease sera were also decreased. To further characterize the specificity of the humoral immune response against the I. dammini spirochete, 35S-methionine-labeled spirochetal antigens were identified by immunoprecipitation with sera from Lyme arthritis patients. These polypeptides had molecular weights of 62, 60, 47, 37, 22, 18, and 15 kDa, and were not recognized by control sera. We conclude that the ELISA, without absorption, is the best method to assay the humoral immune response in Lyme disease, and we have identified methionine-containing spirochetal polypeptides that may be important in Lyme arthritis.
Since the summer of 1982, we have cultured patient specimens for Lyme disease spirochetes. Of 118 patients cultured, four specimens yielded spirochetes: two from blood, one from a skin biopsy specimen of erythema chronicum migrans (ECM), and one from cerebrospinal fluid. All four isolates appeared identical when examined with a monoclonal antibody. However, attempts to recover the spirochete from synovium or synovial fluid were unsuccessful. In addition, the organism could not be visualized in skin or synovial biopsy specimens using the avidin-biotin peroxidase complex detection system. Thus, the current yield in culturing spirochetes from patients is quite low, and it is not yet known whether the organism is still alive later in the disease when arthritis is present.
A case of pigmentary retinal degeneration causing blindness in early childhood, progressive neurosensory hearing loss, diabetes mellitus, acanthosis nigricans, hypogonadism with normal secondary sex characteristics, and kyphoscoliosis without polydactyly and with no mental retardation is reported. The results of endocrinological studies, karyotype analysis, and digital dermatoglyphics supported the clinical diagnosis of the Alström syndrome. The patient had small globes, bilateral posterior subcapsular cataracts, lacy vacuolation of the iris, ciliary process hyalinisation, unilateral asteroid hyalosis, total absence of rods and cones, intraretinal melanin pigment, retinal pigment epithelium atrophy, focal chorioretinal fusion, preretinal fibrosis, bilateral giant optic disc drusen, and optic nerve atrophy. Electron microscopy of the retina demonstrated large numbers of melanolysosomes, numerous folds of basement membrane material, disruption of Bruch's membrane, and numerous bundles of extracellular collagen fibrils in the retinal pigment epithelium.
Forty-three infants and children with bacterial meningitis were treated intravenously with 200 mg of amoxicillin sodium per kg per day for 10 days. (Patients were initially treated with ampicillin and chloramphenicol until the bacterial etiology was defined.) Patients were randomly treated with amoxicillin only or with amoxicillin and four doses of probenecid (10 mg/kg per dose) orally every 6 h for 24 h before the lumbar puncture at day 10. Serum and cerebrospinal fluid (CSF) were obtained on days 1, 5, and 10 of therapy for antibiotic assay. The mean peak serum concentration of amoxicillin of 49.2 micrograms/ml was increased to 61.4 micrograms/ml in patients who received probenecid. The half-life in serum (1.5 h) and area under the curve with probenecid (112.5 micrograms/ml-h) were increased compared with those of amoxicillin alone (1.3 h and 82.2 micrograms/ml-h). The mean peak CSF concentrations on days 1 and 5 were similar, but day 1 concentrations remained between 2.0 micrograms/ml and 5.0 micrograms/ml throughout the 4 h after a dose, whereas the day 5 values decreased at the same decay rate as that in serum. All CSF concentrations were lower on day 10, but patients receiving probenecid had peak values occurring at 1 hr rather than at 0.5 h, and levels were significantly greater at 1 and 2 h after a dose. There were no deaths and patients responded well to treatment.
To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers.
OZ439 was administered as single oral daily doses of a capsule formulation (50–1200 mg) or an oral dispersion (400–1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200–800 mg day−1). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS.
The pharmacokinetic (PK) profile of OZ439 was characterized by a tmax of around 3 h, followed by a multiphasic profile with a terminal half-life of 25–30 h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t1/2 of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites.
The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.
healthy subjects; OZ439; phamacokinetics; safety; synthetic ozonide