[Show abstract][Hide abstract] ABSTRACT: Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by the reports of neuropsychiatric adverse events in patients with influenza. In addition, a recent pre-clinical study in rodents suggested a hypothermic effect of oseltamivir. The current studies investigated the CNS effects, body temperature effect and toxicokinetic profile of oseltamivir in rats. The CNS/temperature study included three groups receiving oseltamivir (500, 763 and 1000 mg/kg free base by oral gavage), one vehicle/control group and one reference group (D-amphetamine, 10 mg/kg). CNS parameters (behaviour, motor activity and co-ordination and sensory/motor reflex responses) and rectal temperature were measured at baseline and at five intervals until 8 hr after dosing. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1000 mg/kg free base. Plasma, cerebrospinal fluid (CSF) and perfused brain concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured until 8 hr after dosing. Median scores for CNS parameters were similar in controls and animals receiving oseltamivir at all time points. Oseltamivir had no physiologically relevant effect on body temperature, but induced a short-lived and small dose-independent decrease in temperature in all active treatment groups at 1 hr after dosing only. Plasma concentrations of OC were higher than of oseltamivir, but the reverse was true in CSF and brain. CNS penetration was low for both moieties. In rats, oseltamivir at supratherapeutic doses up to 1000 mg/kg free base did not exert any effects on CNS function or hypothermic effects and led to limited CNS exposure, resulting in large safety margins.
[Show abstract][Hide abstract] ABSTRACT: Pharmacokinetic-pharmacodynamic relationships are crucial in understanding a drug's arrhythmogenic potential. Models assist to quantitatively relate parent and metabolite concentrations to adverse electrocardiographic effects, including an apparent delay between effect and circulating parent species concentration. Here, we used an effect compartment model to investigate PR and QRS prolongation previously observed in preclinical studies with the NK1-NK3 antagonist R1551.
Using a cross-over design, beagle dogs received a single oral dose of R1551 (0-100mg/kg), and cynomolgus monkeys received oral doses of 0-30 mg/kg once daily for 5 days. PR and QRS intervals and heart rate were measured by telemetry, for ≥ 24h after each dose in dogs, and on treatment days 1, 3, and 5 in monkeys. Pharmacokinetic parameters were estimated by fitting a two-compartment model to the data. For each species, a linear effect compartment model was used to relate PR and QRS intervals to effect compartment concentrations.
The effect compartment model provided a good fit to the observed data for both ECG parameters in dogs, and for QRS interval in monkeys (PR(0)=95.1 ms ± 2.74 and 64.9 ms ± 1.46, QRS(0)=42.5 ms ± 1.24 and 46.5 ms ± 1.11 in dog and monkey, respectively). For PR interval in monkeys, the fit was improved by adding a placebo effect compartment to the linear model. R1551 effects on intervals in dogs suggested the presence of responder and non-responder sub-populations. In monkeys, only the highest R1551 dose prolonged PR intervals. Effect slope factors were similar between dog and monkey for both intervals (S(PR)=0.00930 ms mg(-1)kg(-1)l(-1) ± 0.00133 in dog and 0.00934 ms mg(-1)kg(-1)l(-1) ± 0.00141 in monkey; S(QRS)=0.00274 ms mg(-1)kg(-1)l(-1) ± 0.00101 in dog and 0.00200 ms mg(-1)kg(-1)l(-1) ± 0.000552 in monkey).
Our results indicate a non-linear relationship between R1551 plasma kinetics and electrophysiological effects and suggest that the parent was not responsible for the observed ECG effects. In addition, the population based approach allows exploitation of sparse PK data in dog and monkey, analysis throughout the complete effect time course, and assessment of inter-individual variability, all in a single comprehensive model.
No preview · Article · Feb 2011 · Journal of pharmacological and toxicological methods
[Show abstract][Hide abstract] ABSTRACT: This study compared torcetrapib-induced blood pressure (BP) changes simultaneously obtained by high-definition oscillometry (HDO) and telemetry. Male beagles (n = 6) received single oral doses of vehicle or torcetrapib at 10 or 30 mg/kg; BP were acquired simultaneously by HDO and telemetry from 2 h before dosage until 7 h afterward. Systolic, diastolic, and mean arterial pressures (MAP) and heart rate were compared by using Altman-Bland agreement analysis. Dogs were allocated into subgroups according to temperament and baseline MAP (less than 110 mm Hg and 110 mm Hg or greater). Both methods demonstrated high precision. HDO recordings exhibited higher variability for all parameters (inclusive MAP SDs were 7.0 +/- 2.7 mm Hg for HDO compared with 3.4 +/- 1.9 mm Hg for telemetry), accompanied by a positive bias for all pressures (systolic, 10.4 mm Hg; diastolic, 5.7 mm Hg; MAP, 1.9 mm Hg). Both methods detected similar maximal increases in MAP with 30 mg/kg torcetrapib (HDO, 15.8 +/- 10.4 mm Hg; telemetry, 15.8 +/- 5.3 mm Hg). No significant effects were noted for heart rate. Torcetrapib elicited a dose-dependent increase in BP in dogs with baseline MAP of less than 110 mm Hg, whereas increases were maximal with 10 mg/kg in the other group, and dose-dependence was no longer observed. BP changes were influenced by animal temperament, demonstrating that HDO results must be interpreted with caution. HDO may provide a useful and accurate method for noninvasive BP measurements in canine studies.
Full-text · Article · Jul 2010 · Journal of the American Association for Laboratory Animal Science: JAALAS
[Show abstract][Hide abstract] ABSTRACT: Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
[Show abstract][Hide abstract] ABSTRACT: Biological therapeutic agents (biologicals), such as monoclonal antibodies (mAbs), are increasingly important in the treatment of human disease, and many types of biologicals are in clinical development. During preclinical drug development, cardiovascular safety pharmacology studies are performed to assess cardiac safety in accord with the ICH S7A and S7B regulations that guide these studies. The question arises, however, whether or not it is appropriate to apply these guidelines, which were devised primarily to standardize small molecule drug testing, to the cardiovascular evaluation of biologicals. We examined the scientific literature and formed a consensus of scientific opinion to determine if there is a rational basis for conducting an in vitro hERG assay as part of routine preclinical cardiovascular safety testing for biologicals. We conclude that mAb therapeutics have very low potential to interact with the extracellular or intracellular (pore) domains on hERG channel and, therefore, are highly unlikely to inhibit hERG channel activity based on their targeted, specific binding properties. Furthermore, mAb are large molecules (> 140,000 Da) that cannot cross plasma membranes and therefore would be unable to access and block the promiscuous inner pore of the hERG channel, in contrast with typical small molecule drugs. Consequently, we recommend that it is not appropriate to conduct an in vitro hERG assay as part of a preclinical strategy for assessing the heart rate corrected QT interval (QTc) prolongation risk of mAbs and other types of biologicals. It is more appropriate to assess QTc risk by integrating cardiovascular endpoints into repeat-dose general toxicology studies performed in an appropriate non-rodent species. These recommendations should help shape future regulatory strategy and discussions for the cardiovascular safety pharmacology testing of mAbs as well as other biologicals and provide guidance for the preclinical cardiovascular evaluation of such agents.
Full-text · Article · Sep 2008 · Journal of pharmacological and toxicological methods
[Show abstract][Hide abstract] ABSTRACT: Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.British Journal of Pharmacology (2008) 154, 1491–1501; doi:fn8
Full-text · Article · Jul 2008 · British Journal of Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Computational tools for predicting toxicity have been envisaged for their potential to considerably impact the attrition rate of compounds in drug discovery and development. In silico techniques like knowledge-based expert systems (quantitative) structure activity relationship tools and modeling approaches may therefore help to significantly reduce drug development costs by succeeding in predicting adverse drug reactions in preclinical studies. It has been shown that commercial as well as proprietary systems can be successfully applied in the pharmaceutical industry. As the prediction has been exhaustively optimized for early safety-relevant endpoints like genotoxicity, future activities will now be directed to prevent the occurrence of undesired toxicity in patients by making these tools more relevant to human disease.
Full-text · Article · May 2008 · Drug Discovery Today
[Show abstract][Hide abstract] ABSTRACT: After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004–5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company’s own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivircarboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS.
In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1 000 000 prescriptions) in children (aged ≤16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged >16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories.
No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n =159 386) was no higher than those not receiving antivirals (n = 159 386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of oseltamivir treatment; events were also similar to those occurring after the initiation of oseltamivir therapy.
No clinically relevant differences in plasma pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both oseltamivir and oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting oseltamivir to oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain: plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to ≥100 times the clinical dose. Oseltamivir or oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs.
The available data do not suggest that the incidence of NPAEs in influenza patients receiving oseltamivir is higher than in those who do not, and no mechanism by which oseltamivir or oseltamivir carboxylate could cause or worsen such events could be identified.