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Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallel-group study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.
Vicriviroc maleate is a novel CCR5 antagonist that is currently in late-stage clinical development as part of a ritonavir-boosted protease inhibitor regimen for HIV-1-infected individuals. In clinical studies, vicriviroc has demonstrated potent and durable virologic suppression, immunologic activity, and generally favorable tolerability (5).
The current report describes two phase I studies that investigated the cardiac and central nervous system (CNS) safety, respectively, of vicriviroc in normal healthy adult volunteers. The first study was performed in accordance with the standard guidance for industry, which requires a comprehensive evaluation of cardiac safety for the safe conduct of drug development programs and drug registration, including those for vicriviroc (9). These assessments characterize the potential for new agents to prolong the QT/corrected QT (QTc) interval and to induce cardiac arrhythmias, such as torsade de pointes (TdP) and other ventricular tachyarrhythmias (1, 2, 8). Vicriviroc was studied both at a supratherapeutic dose and at the intended clinical dose in comparison with a placebo (negative control) and moxifloxacin (positive control). The effect of vicriviroc was evaluated in the presence of ritonavir, since the intended clinical administration of vicriviroc is to be part of an antiretroviral regimen that includes a ritonavir-boosted protease inhibitor (PI).
The second, independent study was performed to evaluate the CNS safety of vicriviroc, since the dose-limiting toxicity for vicriviroc in nonclinical safety evaluations was seizures, although no seizures have been seen clinically in any patient treated with vicriviroc and there has been no evidence of a clinically significant CNS effect in humans (4). Seizures observed in several animal species were characterized as tonic-clonic convulsions, occurred generally at the time of maximal plasma drug concentrations, were self-limiting, and were preventable with standard anticonvulsant therapy. The mechanism by which vicriviroc caused seizures in animals is not clear. Animal-to-human exposure multiples (based on the pharmacokinetic concentration value associated with seizure activity in the dog) are ≥10 based on the intended clinical usage of 30 mg of vicriviroc as part of a ritonavir-boosted PI-containing antiretroviral regimen. To further characterize vicriviroc, we performed clinical assessments of the safety of both single and multiple supratherapeutic doses of vicriviroc, including electroencephalogram (EEG) monitoring.
The cardiac safety study enrolled healthy adult subjects aged 18 to 50 years with a body mass index of 19 to 32 kg/m2. Results from clinical laboratory tests, physical examinations, and electrocardiograms (ECGs) had to be within the normal range or acceptable to the investigator. All subjects were required to have ECG conduction intervals within gender-specific normal ranges at screening (≤430 ms for males; ≤450 ms for females). Criteria for exclusion included a history of seizures or significant head trauma; positive serology for hepatitis B, hepatitis C, or HIV; a history of risk factors for TdP; or a history of drug or alcohol abuse within the past 2 years.
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Independent Ethics Committee at the study center. Written informed consent was obtained from all subjects prior to any study-related activities at the screening visit.
This randomized, partially blind (open-label for placebo and positive controls), parallel-group study conducted at a single study center was designed to evaluate QT/QTc interval prolongation and proarrhythmic potential for vicriviroc in the presence of ritonavir at a supratherapeutic dose in healthy subjects by using a placebo control and moxifloxacin as the positive control. Secondary endpoints included the QT/QTc interval prolongation and proarrhythmic potential for vicriviroc at the clinically therapeutic dose in the presence of ritonavir, the QT/QTc interval prolongation and proarrhythmic potential for ritonavir alone at a commonly used clinical dose (i.e., 100 mg), the safety and tolerability of vicriviroc in the presence of ritonavir, and the pharmacokinetics of vicriviroc-ritonavir after multiple doses (i.e., on day 10). Subjects meeting the entry criteria were randomized equally to 1 of 5 treatments for 10 days: (i) a moxifloxacin-matched placebo for 9 days and a single dose (SD) of moxifloxacin (400 mg) on day 10 (positive control); (ii) a moxifloxacin-matched placebo control; (iii) vicriviroc-ritonavir at a clinically therapeutic dose (30 and 100 mg); (iv) vicriviroc-ritonavir at a supratherapeutic dose (150 and 100 mg); and (v) ritonavir alone (100 mg). All doses of study drugs were to be administered in the morning (~8 to 9 a.m.) after a fast of approximately 10 h. Subjects were to remain at the study center through the morning of day 12 (i.e., approximately 48 h after the last dosing) for pharmacodynamic, pharmacokinetic, and safety assessments prior to being discharged; subjects were to return to the clinic for final assessments on day 15.
Since there were no prior safety data for the supratherapeutic dose of 150 mg of vicriviroc in the presence of ritonavir, the study commenced with 3 cohorts of 10 subjects, each equally randomized into the 5 treatment arms such that only 2 subjects in each cohort received the supratherapeutic dose. Once the preliminary safety and pharmacokinetic data from these first cohorts were reviewed and no concerning signals were noted, the remainder of the cohorts could be filled.
Volunteers were screened within 3 weeks of dosing, and eligible subjects were to be confined at the study center beginning on day −2 for study admission assessments. Approximately 12 h after admission to the clinic (on day −1), subjects who continued to qualify for the study were to begin baseline 24-h continuous ECG recordings. The start of these ECG recordings was to be timed so that they ended before the first dose of study medication on day 1. The ECGs were conducted via a 12-lead digital Holter monitor, which recorded high-resolution (1,000-Hz) data on a memory card. The nominal times for ECG extractions on day −1 were to correspond to those planned for a posttreatment 24-h continuous ECG conducted on day 10—that is, at 0 h (predose) and 1, 1.5, 2, 3, 6, 12, and 23 h after dosing on day 10. The schedule and content of meals and snacks (including a 4-h postdose fast planned for day 10) and the schedule of resting periods (i.e., 10 min before and 10 min after nominal ECG extraction times) on day −1 were also to match those planned for day 10.
In addition to ECG monitoring, the evaluation of safety included physical examinations, vital-sign assessments, and laboratory tests conducted at screening and at scheduled times during the study. All clinical and laboratory adverse events (AEs) observed for all subjects during the study were recorded, as was the use of any concomitant medications. All adverse events, including treatment-related adverse events, were tabulated by treatment group and severity.
Blood samples for pharmacokinetic analyses were obtained on day 1 (before dosing) and on day 10 (at specific times before dosing through 24 h after dosing). The pharmacokinetic parameters determined for vicriviroc and ritonavir after multiple doses (on day 10) included the maximum observed concentration (Cmax) in plasma, the maximum predose concentration (Cmin), the time to Cmax (Tmax), and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24).
Based on an assumed pooled standard deviation of 12 ms, a sample size of 200 subjects—40 subjects in each of 5 treatment groups—was estimated to provide at least 80% power to conclude that there is no QTc interval prolongation effect from the drug. This calculation assumed an increase of at most 2 ms in the QTc interval for the supratherapeutic dose of vicriviroc-ritonavir versus placebo.
ECG recordings were evaluated by a blinded third party in order to obtain measurements of the RR, PR, QRS, and QT intervals and the derivation of the heart rate and the QTc interval. The QT interval using Fridericia's correction formula (QTcF) was used as the primary measure of change in the QT interval. Changes from baseline for each of the ECG parameters, averaged per day and at each of the time-matched intervals, were summarized using descriptive statistics.
The derived QTc interval was analyzed separately by time using a one-way analysis-of-variance (ANOVA) model that extracted the effect due to treatment. The ANOVA was performed both with and without the use of the baseline value as a covariate. The difference between vicriviroc with ritonavir, ritonavir alone, or moxifloxacin, on the one hand, and the placebo, on the other, in terms of the change from the time-matched baseline QTc interval and the corresponding 95% one-sided confidence interval (CI), was provided at the 8 time points at which ECG recordings were extracted on day 10: 0, 1, 1.5, 2, 3, 6, 12, and 23 h after dosing. Analyses were performed separately for males and females.
If the largest upper bound of the one-sided 95% CIs for the difference in the change from the time-matched baseline QTc interval between vicriviroc-ritonavir and the placebo was less than 10 ms, then combination therapy with vicriviroc and ritonavir was considered to have no QTc interval prolongation effect. The primary comparison was that between the supratherapeutic dose of vicriviroc (150 mg) with ritonavir and the placebo. The comparison between moxifloxacin and the placebo was used to verify the QTc interval prolongation effect of moxifloxacin and therefore to validate the ability of the study to detect a difference. The comparison between ritonavir and the placebo was used to characterize the effect of ritonavir alone on the QTc interval.
The CNS safety study enrolled healthy adult subjects aged 18 to 48 years with a body mass index of 19 to 32 kg/m2. Results from clinical laboratory tests, physical examinations, and electrocardiograms had to be within the normal range or acceptable to the investigator. All subjects were required to have QTc conduction intervals within gender-specific normal ranges at screening (≤430 ms for males; ≤450 ms for females). In addition, subjects had to have a standard EEG at screening that was strictly normal under resting conditions as well as during hyperventilation and intermittent photic stimulation (IPS). Criteria for exclusion included treatment with any medication known to induce or inhibit CYP450 3A4 or to have CNS effects within 2 to 6 weeks prior to drug administration; a personal or family history of seizures, head trauma, or CNS infection; a history of drug or alcohol abuse within the past 2 years; a positive drug screen; blood donation within 60 days prior to drug administration; positive serology for hepatitis B, hepatitis C, or HIV; and smoking of more than 10 cigarettes (or equivalent tobacco use) per day.
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Independent Ethics Committee at the study center. Written informed consent was obtained from all subjects prior to any study-related activities at the screening visit.
This randomized, third-party-blind, placebo-controlled, parallel-group study conducted at a single study center was designed to assess the CNS effect of single and multiple doses of vicriviroc, specifically the occurrence or nonoccurrence of clinical seizure, based on safety monitoring of healthy volunteers by EEG. Secondary endpoints included the safety, tolerability, and pharmacokinetics of vicriviroc after single-dose and multiple-dose administration.
Enrollment was planned for 40 subjects: 10 subjects (5 men, 5 women) in each of 4 cohorts with vicriviroc dose levels escalating by at least 50 mg in each cohort. Subjects were randomized within each sex in a 4:1 ratio to vicriviroc or placebo. Cohorts of 10 subjects were assigned to receive single and multiple doses of vicriviroc (8 subjects in each cohort) or placebo (2 subjects in each cohort), with single- and multiple-dose periods separated by at least 7 days. The doses were to be administered to each of the cohorts according to the following schedules: for cohort 1, a single dose (SD) of 200 mg, followed by washout and then 150 mg once daily (QD) for 7 days; for cohort 2, a 250-mg SD, washout, and 200 mg QD for 7 days; for cohort 3, a 300-mg SD, washout, and 250 mg QD for 7 days; and for cohort 4, a 400-mg SD, washout, and 300 mg QD for 7 days. The decision to proceed to the next dose level cohort was to be based on a review of all available safety data from the previous dose level. If any patient experienced a clinical seizure, then the blind was to be broken for that subject; if the subject had received vicriviroc, then the study was to be stopped. If any patient had abnormal epileptiform activity without clinical symptoms, then the study was to continue according to the protocol; however, the neurologist could stop treatment at any time if he or she deemed it to be medically appropriate.
All doses of study drugs were to be administered in the morning (~9 a.m.); a 10-h overnight fast before dosing was required on days with EEG recordings. Subjects were to remain at the study site beginning 36 h before dosing and continuing through 72 h following administration of the single dose in period 1 and the final dose in period 2.
Continuous EEGs, including basic, IPS, and hyperventilation components, were performed at screening over a 30-min period. Continuous 4-h safety EEGs were performed on day 1 during period 1 and on days 1 and 7 during period 2. Electrodes for the EEG were placed on the scalp according to the 10-20 international system (6). Safety EEG recordings were examined, specifically for the presence of any epileptiform activity, which was to be reported as an adverse event.
In addition to safety monitoring by EEG, the evaluation of safety included multiple time-matched ECGs at baseline and throughout the study, as well as physical examinations, vital-sign assessments, and laboratory tests conducted at screening and at scheduled times during the study. All clinical and laboratory adverse events observed for all subjects during the study were recorded. All adverse events, including treatment-related adverse events, were tabulated by treatment group and severity.
Blood samples for pharmacokinetic analyses were obtained throughout day 1 of both treatment periods, throughout day 7 of period 2, and up to 72 h after the final dose of each period. The pharmacokinetic parameters determined for vicriviroc after single and multiple doses included the Cmax, AUC, Tmax, and Cmin. In addition, a single sample of cerebrospinal fluid (CSF) was collected according to a standardized procedure on day 6 of period 2 at an appropriate time between 1 and 4 h after dosing (the approximate plasma Tmax) in order to determine the vicriviroc concentration in the CSF compartment.
The cardiac safety study enrolled 200 healthy subjects (110 males, 90 females) between the ages of 18 and 50 years (mean age, 30.8 years). A total of 154 subjects (77%) were white; 42 subjects (21%) were black; 2 (1%) were Native American; and 2 (1%) were multiracial. All demographic characteristics for the different treatment groups were similar (Table (Table1).1). A total of 193 subjects completed the study. Seven subjects did not complete the study due to adverse events (n = 3), withdrawal of consent (n = 3), or loss to follow-up (n = 1).
The moxifloxacin treatment arm validated the study methodology in terms of detecting a QT/QTc prolongation effect. The upper bound of the one-sided 95% CI for the mean difference between moxifloxacin and the placebo (for the change in the QTcF interval from baseline to day 10) at 1, 1.5, 2, 3, 6, and 12 h was greater than 10 ms, which is the standard threshold for an effect, as defined by the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH-E14) (9). In addition, the mean difference between moxifloxacin and the placebo was greater than 10 ms at 1, 1.5, 2, and 3 h postdose.
Neither treatment group receiving vicriviroc (at a supratherapeutic or a therapeutic dose) concomitant with ritonavir showed a substantial difference from the placebo group in the mean change in the QTcF interval after 10 days of dosing; the mean difference did not exceed 4.3 ms. The upper bound of the one-sided 95% CI for the mean difference in the QTcF interval between each vicriviroc-ritonavir treatment group and the placebo group was less than 10 ms at all time points and did not exceed 7.8 ms. For ritonavir alone, the upper bound of the one-sided 95% CI for the mean QTcF interval difference compared with that for the placebo was also less than 10 ms at all time points. Figure Figure11 depicts the mean QTcF interval change from baseline and the one-sided 95% CIs for all treatments compared with the placebo for the model using the baseline value as a covariate. Similar values were obtained for the model not using the baseline QTcF interval value as a covariate. In addition, an evaluation of the QTcF interval according to sex yielded results similar to those of the combined analysis.
No subject had a QT interval, either uncorrected or corrected, that exceeded 500 ms or that changed by >60 ms from the baseline value. Categorical analysis of changes in the QT interval established that the numbers of subjects with changes of 0 to 30 ms were similar across treatment groups (Table (Table2).2). Changes of 31 to 60 ms occurred in no more than 2 subjects in any group, none of whom was treated with vicriviroc-ritonavir.
All treatments were well tolerated, including the supratherapeutic dose of vicriviroc administered concomitantly with ritonavir. Most treatment-emergent adverse events (TEAEs) in all groups were mild and resolved without intervention, and the rates of these events were similar among the 3 groups treated with vicriviroc and/or ritonavir. No serious adverse events or deaths were reported. The most commonly reported TEAEs included gastrointestinal effects, such as nausea, that are typically observed with the use of ritonavir, as well as nervous system effects, predominantly headache and dizziness. TEAEs occurring in at least 10% of subjects in any treatment group are shown in Table Table3.3. One subject with no reported subjective symptoms experienced a cardiac treatment-emergent adverse event—mild palpitations—during the receipt of vicriviroc-ritonavir at 150 and 100 mg; this event lasted 2 days and was considered to be possibly related to treatment. The subject had sporadic sinus bradycardia recorded over approximately 1 h on the morning of day −1 and mildly depressed calcium levels on 3 occasions before, during, and after treatment. The QTcF intervals for this subject were normal both on day 1 (range, 408 to 427 ms) and on day 10 (range, 397 to 410 ms). No remarkable patterns pertaining to vital signs or laboratory tests were observed across the subjects.
Three subjects were discontinued from the study because of TEAEs. One subject in the vicriviroc-ritonavir (150 and 100 mg) group stopped the study drugs after 5 days because of mild angioedema of the lower right lip that began on day 3; this TEAE, which was considered possibly related to the study treatment, lasted for 3 days and was treated with diphenhydramine. One subject in the ritonavir group stopped the study drug after 3 days because of a transient episode of moderate vomiting on day 2; this TEAE was considered possibly related to the study treatment. Another subject in the ritonavir group stopped the study drug after 4 days due to transient mild myalgia in the right calf that began on day 2; this TEAE was considered unrelated to the study treatment.
Vicriviroc was rapidly absorbed following oral administration, and low variability in Cmax, Cmin, and AUC0-24 was observed between subjects based on the coefficient of variation (CV) (Table (Table4).4). The maximum plasma Cmax measured at each dose level was 622 ng/ml for 30 mg of vicriviroc and 2,470 ng/ml for 150 mg of vicriviroc, in the presence of ritonavir. The mean Cmax (CV) was 403 ng/ml (21%) for 30 mg of vicriviroc and 1,900 ng/ml (15%) for 150 mg of vicriviroc, in the presence of ritonavir. Vicriviroc exposure was dose-proportional, with a 5-fold increase in dosage resulting in approximately 5-fold increases in Cmax and AUC0-24. Similar ritonavir exposures were observed whether ritonavir was administered alone or with vicriviroc (data not shown).
The CNS safety study enrolled 30 healthy subjects (15 males, 15 females) between the ages of 18 and 48 years (mean age, 30.7 years). The study population was predominantly white (18 subjects [60%]), with 8 black subjects (27%), 2 Asian subjects (7%), 1 Native American subject (3%) and 1 Native Hawaiian/Pacific Islander subject (3%). The median body mass index was 24.65 mg/kg2 (range, 19.4 to 32.2 mg/kg2). All demographic characteristics were similar for the different treatment groups (Table (Table5).5). A total of 27 subjects completed the study. Three subjects did not complete the study due to adverse events (n = 1), administrative reasons (n = 1), or a personal decision (n = 1).
Three cohorts of 10 subjects each were assigned to receive single and multiple doses of vicriviroc (8 subjects in each cohort) or placebo (2 subjects in each cohort). The doses of vicriviroc administered in the 3 cohorts were as follows: for cohort 1, a single dose (SD) of 200 mg, followed by washout and then 150 mg once daily (QD) for 7 days; for cohort 2, a 250-mg SD, washout, and 200 mg QD for 7 days; and for cohort 3, a 300-mg SD, washout, and 250 mg QD for 7 days. The single- and multiple-dose periods were separated by at least 7 days. The fourth dose level cohort was not enrolled based on the initial readings of potentially aberrant waveforms (discussed in detail below).
No seizure activity was noted in any subject at any dose of vicriviroc during the course of this study. All EEGs were initially interpreted by a board-certified neurologist who was also certified in electroencephalography at the study site as per the protocol. The initial read by the consulting site neurologist noted isolated aberrant EEG waveforms for 4 subjects receiving a 300-mg SD of vicriviroc followed by 250 mg QD; these were reported as AEs. Follow-up EEGs were recorded for all 4 subjects. One of these subjects was discontinued from the study after receiving a single 300-mg dose of vicriviroc on the basis of this reported AE. Two independent neurologists/electroencephalographers were subsequently commissioned to review the EEG tracings in a blinded manner; one reviewer assessed only the EEG waveforms initially deemed aberrant, and the other reviewer evaluated all EEGs from the study. Both reviewers were blinded to the study design, the timing of tracings, the treatment assignment, and the initial interpretations of the waveforms. A third independent neurologist/electroencephalographer was commissioned to review all the preclinical and clinical data from the program as a whole, as well as the tracings and reports by the other neurologists, as part of a comprehensive risk assessment of vicriviroc for humans.
The neurologists commissioned to review the EEG tracings did so independently, and there was a certain lack of consensus among the reviewers as to whether waveforms were normal or aberrant. One reviewer noted aberrancy in both a screening (predrug) and an on-treatment waveform for one subject that was not considered aberrant by other reviewers. However, all reviewers independently concluded that the original findings were not clinically relevant, and they characterized the findings reported as aberrant waveforms as subtle and within the range of normal and expected variations for drowsy/awake states in adults.
Vicriviroc was safe and well tolerated when administered as a single dose up to 300 mg and as a multiple dose up to 250 mg. A total of 29 subjects (97%), including all 6 subjects (100%) receiving the placebo, reported at least 1 adverse event during the study. The majority of adverse events were reported as mild, and no deaths or other significant adverse events were reported. The most common adverse events included headache (14 subjects [47%]); back pain (6 subjects [20%]); nausea, fatigue, pollakiuria (extraordinary urinary frequency), and puncture site pain (5 subjects [17%] for each); abnormal EEG (4 subjects [13%]); and increased blood creatine phosphokinase (3 subjects [10%]). Treatment-emergent adverse events considered related to treatment occurring in at least 10% of subjects in any treatment group are shown in Table Table6.6. No clinically significant changes in blood chemistries or hematologic parameters, vital signs, or ECGs were noted in any treatment group. In addition, no subject had a prolonged QTcF interval (>430 ms for males, >450 ms for females) at any time during the study.
The peak plasma vicriviroc concentration was observed at a median of 2 h following single-dose administration (Table (Table7).7). The maximum plasma Cmax was 1,460 ng/ml after a single dose of 300 mg vicriviroc and 1,300 ng/ml after 7 days of 250 mg QD; mean Cmax values (CV) were 1,130 ng/ml (29%) in the single-dose 300-mg group and 1,040 ng/ml (18%) after 7 days of 250 mg QD. The mean terminal half-life values of vicriviroc following oral administration of the single 200-mg, 250-mg, and 300-mg doses were 24.0, 27.0, and 27.4 h, respectively. The mean apparent volume of distribution (V/F) ranged from 762 to 1,010 liters. For comparison purposes, the steady-state mean Cmax in plasma at the intended clinical dose of 30 mg vicriviroc plus 100 mg ritonavir is approximately 372 ng/ml based on prior pharmacokinetic studies (Merck Pharmaceuticals, data on file). This was exceeded at all doses in the EEG study.
The peak concentration of vicriviroc in plasma was observed at a median of 1.5 to 2 h following multiple-dose administration. The mean terminal half-life values of vicriviroc following multiple oral administrations ranged from 23.7 to 28.2 h. The mean accumulation ratio ranged from 1.60 to 1.76. Steady-state vicriviroc concentrations were achieved by day 7, based on trough concentrations. For each subject, the vicriviroc concentration measured in CSF was comparable to concurrently measured concentrations in plasma.
Rigorous evaluation of the safety properties of a novel agent is a standard component of the drug development process; routine assessments include general safety and effects on cardiac conduction. The adverse events reported in the current studies were generally mild in severity and resolved without the need for intervention. No serious adverse events or deaths were reported in either study. The safety results from both studies demonstrated that vicriviroc was safe and well tolerated at multiple doses as high as 150 mg when administered with ritonavir, and at single doses as high as 300 mg and multiple doses as high as 250 mg when administered without ritonavir. Both studies also showed that vicriviroc exposure is associated with relatively low intersubject variability. Efficacy and safety results from phase II trials support a dose of 30 mg once daily as part of a ritonavir-boosted protease inhibitor-containing regimen.
To assess cardiac conduction, a thorough QT/QTc study is typically conducted during early clinical development of a novel agent to determine whether the drug induces a threshold pharmacologic effect on cardiac repolarization, which is indicated by QT/QTc prolongation (9). During the assessment of the drug in healthy subjects, the threshold level of QT/QTc prolongation that is cause for regulatory concern is approximately 5 ms, as evidenced by an upper bound on the 95% CI around the mean effect on QTc of 10 ms.
The thorough QT study confirmed the cardiac safety of vicriviroc. The inclusion of a moxifloxacin treatment arm as a positive control validated the sensitivity of the study for the detection of a QT/QTc prolongation effect, and the effects of moxifloxacin on the QT/QTc interval were consistent with those reported previously (3, 7). This study showed that vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose in combination with ritonavir. The exposure to vicriviroc associated with the supratherapeutic dose is about five times that of the therapeutic dose; this exposure provides a substantial therapeutic index for cardiac conduction liability and general safety. These findings were similar for males and females. The latter is a notable finding, since evidence suggests that women are at a significantly greater risk of QT interval prolongation than men and also exhibit a higher incidence of drug-induced TdP (8, 10). Notably, the mechanisms responsible for this sex difference are not known.
During the course of development, unexpected preclinical safety signals are not uncommon and often need to be explored in the clinic. In the current CNS study, the preclinical signal of seizure activity was evaluated for its relevance to humans. This study offered a very controlled opportunity to assess the convulsive potential of vicriviroc in humans. There is no evidence of translatability of seizure activity to humans based on the results of the current study and the results of the phase II trial and ongoing clinical studies with vicriviroc (11).
The absence of CNS adverse events with high plasma exposures in the cardiac study supports the findings of the CNS study. No seizure activity was noted in either study, and in the CNS study, in which serial EEG assessments were included to improve upon the gross ability of clinicians to detect adverse effects, no definite epileptiform activity was seen in any individual. The EEG findings from four individuals, which were initially reported as aberrant, were deemed not clinically relevant by several highly experienced electroencephalographers who subsequently reviewed them. In the opinion of the reviewers, the waveforms were well within the range of normal and expected variations for drowsy and awake states in adults. These EEG findings did not approach the level of relevance noted for epileptogenic compounds such as clozapine, for which the findings are frank and obvious and have an established relationship to the drug dose and concentration.
The CNS safety findings in the current study confirm the results of an earlier study of single-dose vicriviroc in which lower doses were investigated (study P03161; data on file). In the earlier study, plasma vicriviroc concentrations as high as 819 ng/ml after administration of a single 150-mg dose were not associated with clinical signs or symptoms or with aberrant EEG spike and wave activity, even with intermittent photic and hypocapnic stimulation. Moreover, vicriviroc was not associated with changes in critical thresholds for CNS excitability or with systemic modifications in low EEG frequencies after single doses as high as 150 mg, based on quantitative EEG analysis (unpublished data). The observed band patterns were consistent with a lack of subclinical-level seizure-related activity. The lack of clinical significance of the EEG findings observed in the present CNS safety study and the lack of documented drug-related seizure activity throughout the clinical vicriviroc program as a whole give confidence that the preclinical CNS toxicology findings are not predictive of clinical experience and that special measures are not indicated in further clinical study beyond avoidance of exposure of populations at increased risk of seizure activity and careful monitoring and follow-up of treated patients.
In summary, the results of these studies show that vicriviroc, with or without ritonavir, produces no clinically relevant cardiac or CNS effects in healthy individuals at exposures (or doses) up to about 5 times the exposure (or dose) expected in clinical practice with HIV-infected patients.
We thank Angela Sansone-Parsons, Peter W. Kaplan, and Gregory Lewis Krauss for their contributions to this study.
Assistance with manuscript preparation, funded by Schering-Plough Corporation, now Merck & Co., Inc., was provided by Sui Generis Health (New York, NY).
Published ahead of print on 29 March 2010.