BAXDELA Tablet / Powder for solution for injection Ref.[9994] Active ingredients: Delafloxacin

The antibacterial activity of delafloxacin appears to best correlate with the ratio of area under the concentration-time curve of free delafloxacin to minimal inhibitory concentration (fAUC/MIC) for Gram-positive organisms such as Staphylococcus aureus and Gram-negative organisms such as Escherichia coli based on animal models of infection.

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled, thorough QT/QTc study, 51 healthy subjects received BAXDELA 300 mg IV, BAXDELA 900 mg IV, oral moxifloxacin 400 mg, or placebo. Neither BAXDELA 300 mg nor BAXDELA 900 mg (three times the intravenous therapeutic dose) had any clinically relevant adverse effect on cardiac repolarization.

Photosensitivity Potential

A study of photosensitizing potential to ultraviolet (UVA and UVB) and visible radiation was conducted in 52 healthy volunteers (originally 13 subjects per treatment group). BAXDELA, at 200 mg/day and 400 mg/day (0.22 and 0.44 times the approved recommended daily oral dosage, respectively) for 7 days, and placebo did not demonstrate clinically significant phototoxic potential at any wavelengths tested (295 nm to 430 nm), including solar simulation. The active comparator (lomefloxacin) demonstrated a moderate degree of phototoxicity at UVA 335 nm and 365 nm and solar simulation wavelengths.

The pharmacokinetic parameters of delafloxacin following single- and multiple-dose (every 12 hours) oral (450 mg) and intravenous (300 mg) administration are shown in Table 6. Steady-state was achieved within approximately three days with accumulation of approximately 10% and 36% following IV and oral administration, respectively.

Table 6. Mean (SD) Delafloxacin Pharmacokinetic Parameters Following Single and Multiple Oral and Intravenous Administration:

C_max = maximum concentration; T_max = time to reach C_max; AUC = area under the concentration-time curve; CL = systemic clearance; CL/F = apparent oral clearance; R_ac = accumulation ratio
* Q12h is every 12 hours
^† Median (range)
^‡ AUC is AUC_τ (AUC from time 0 to 12 hours) for single dose and multiple-dose administration
^§ CL is reported for intravenous injection. CL/F is reported for tablet

Absorption

The absolute bioavailability for BAXDELA 450 mg oral tablet administered as a single dose was 58.8%. The AUC of delafloxacin following administration of a single 450 mg oral (tablet) dose was comparable to that following a single 300 mg intravenous dose. The C_max of delafloxacin was achieved within about 1 hour after oral administration under fasting condition. Food (kcal: 917, Fat: 58.5%, Protein: 15.4%, Carbohydrate: 26.2%). did not affect the bioavailability of delafloxacin [see Dosage and Administration (2.1)].

Distribution

The steady state volume of distribution of delafloxacin is 30–48 L which approximates total body water. The plasma protein binding of delafloxacin is approximately 84%; delafloxacin primarily binds to albumin. Plasma protein binding of delafloxacin is not significantly affected by renal impairment.

Following IV administration of 7 doses of 300 mg of BAXDELA to 30 healthy volunteers, the mean BAXDELA AUC_0-12 (3.6 hr*mcg/mL) in alveolar macrophages was 80% of the free-plasma AUC_0-12, and the mean BAXDELA AUC_0-12 (2.8 hr*mcg/mL) in epithelial lining fluid was 70% of the free-plasma AUC_0-12.

Elimination

In a mass balance study, the mean half-life for delafloxacin was 3.7 hours (SD 0.7 hour) after a single dose intravenous administration. The mean half-life values for delafloxacin ranged from 4.2 to 8.5 hours following multiple oral administrations. Following administration of a single 300 mg intravenous dose of BAXDELA, the mean clearance (CL) of delafloxacin was 16.3 L/h (SD 3.7 L/h), and the renal clearance (CLr) of delafloxacin accounts for 35-45% of the total clearance.

Metabolism

Glucuronidation of delafloxacin is the primary metabolic pathway with oxidative metabolism representing about 1% of an administered dose. The glucuronidation of delafloxacin is mediated mainly by UGT1A1, UGT1A3, and UGT2B15. Unchanged parent drug is the predominant component in plasma. There are no significant circulating metabolites in humans.

Excretion

After single intravenous dose of ¹⁴C-labeled delafloxacin, 65% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 28% was excreted in feces as unchanged delafloxacin. Following a single oral dose of ¹⁴C-labeled delafloxacin, 50% of the radioactivity was excreted in urine as unchanged delafloxacin and glucuronide metabolites and 48% was excreted in feces as unchanged delafloxacin.

Specific Populations

No clinical significance in the pharmacokinetics of delafloxacin was observed based on age, sex, race, weight, body mass index, and disease state (ABSSSI and CABP).

Patients with Hepatic Impairment

No clinically meaningful changes in delafloxacin C_max and AUC were observed, following administration of a single 300 mg intravenous dose of BAXDELA to patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, and C) compared to matched healthy control subjects.

Patients with Renal Impairment

Following a single intravenous (300 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m²), moderate (eGFR = 31–50 mL/min/1.73 m²), severe (eGFR = 15-29 mL/min/1.73 m²) renal impairment, and ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before and 1 hour after hemodialysis, mean total exposure (AUC_t) of delafloxacin was 1.3, 1.6, 1.8, 2.1, and 2.6-fold higher, respectively than that for matched normal control subjects. The mean dialysate clearance (CL_d) of delafloxacin was 4.21 L/h (SD 1.56 L/h). After about 4 hours of hemodialysis, the mean fraction of administered delafloxacin recovered in the dialysate was about 19% [see Use in Specific Populations (8.7)].

Following a single oral (400 mg) administration of delafloxacin to subjects with mild (eGFR = 51-80 mL/min/1.73 m²), moderate (eGFR = 31-50 mL/min/1.73 m²), or severe (eGFR = 15-29 mL/min/1.73 m²) renal impairment, the mean total exposure (AUC_t) of delafloxacin was about 1.5-fold higher for subjects with moderate and severe renal impairment compared with healthy subjects, whereas total systemic exposures of delafloxacin in subjects with mild renal impairment were comparable with healthy subjects.

In patients with moderate (eGFR = 31–50 mL/min/1.73 m²), or severe (eGFR = 15–29 mL/min/1.73 m²) renal impairment or ESRD on hemodialysis, accumulation of the intravenous vehicle SBECD occurs. The mean systemic exposure (AUC) increased 2-fold, 5-fold, 7.5-fold, and 27-fold for patients with moderate impairment, severe impairment, ESRD on hemodialysis receiving intravenous delafloxacin within 1 hour before, and 1 hour after hemodialysis respectively, compared to the healthy control group. In subjects with ESRD undergoing hemodialysis, SBECD is dialyzed with a clearance of 4.74 L/h. When hemodialysis occurred 1 hour after the BAXDELA infusion in subjects with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over approximately 4 hours.

Geriatric Patients

Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin C_max and AUC_∞ values in elderly subjects (≥65 years) were about 35% higher compared to values obtained in young adults (18 to 40 years). This difference is not considered clinically relevant. A population pharmacokinetic analysis of patients with ABSSSI or CABP indicated that patients over the age of 65 years have slower clearance than younger patients. However, the overall impact on delafloxacin pharmacokinetics is not considered clinically significant and dose adjustment in elderly patients is not warranted.

Male and Female Patients

Following single oral administration of 250 mg delafloxacin (approximately 0.6 times the approved recommended oral dose), the mean delafloxacin C_max and AUC_∞ values in male subjects were comparable to female subjects. Results from a population pharmacokinetic analysis showed that females have a 24% lower AUC than males. This difference is not considered clinically relevant.

Drug Interaction Studies

Drug Metabolizing Enzymes

Delafloxacin at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in vitro in human liver microsomes. At a delafloxacin concentration (500 µM) well above clinically relevant exposures, the activity of CYP2E1was increased.

In human hepatocytes, delafloxacin showed no potential for in vitro induction of CYP1A2, 2B6, 2C19, or 2C8 but was a mild inducer of CYP2C9 at a concentration of 100 µM and CYP3A4 at a clinically relevant concentration. Administration of BAXDELA 450 mg every 12 hours for 5 days to healthy male and female subjects (n=22) prior to and on Day 6 with a single oral 5 mg dose of midazolam (a sensitive CYP3A substrate), did not affect the C_max and AUC values for midazolam or 1-hydroxy midazolam compared to administration of midazolam alone.

Transporters

Delafloxacin was not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: MDR1, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, OCT1 and OCT2. Delafloxacin was not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP. Delafloxacin was shown to be a substrate of P-gp and BCRP in vitro. The clinical relevance of co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.

Mechanism of Action

Delafloxacin belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature. The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits a concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.

Resistance

Resistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.

Fluoroquinolones, including delafloxacin, have a different chemical structure and mechanism of action relative to other classes of antibacterial compounds (e.g., aminoglycosides, macrolides, β-lactams, glycopeptides, tetracyclines and oxazolidinones).

In vitro resistance to delafloxacin develops by multiple step mutations in the QRDRs of gram-positive and gram-negative bacteria. Delafloxacin-resistant mutants were selected in vitro at a frequency of < 10 ^-9.

Although cross-resistance between delafloxacin and other fluoroquinolone-class antibacterial agents has been observed, some isolates resistant to other fluoroquinolone-class antibacterial agents may be susceptible to BAXDELA including some S. aureus isolates carrying mutations in the quinolone resistance determining region (gyrA, parC and parE).

Additionally, delafloxacin has activity against some isolates of beta-lactamase positive H. influenzae and H. parainfluenzae.

Interaction With Other Antimicrobials

In vitro drug combination studies with delafloxacin and amoxicillin/clavulanate, azithromycin, aztreonam, ceftaroline, ceftazidime, ceftriaxone, colistin, daptomycin, doxycycline, linezolid, meropenem, penicillin, rifampin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin demonstrated neither synergy nor antagonism.

Antimicrobial Activity

BAXDELA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, [see Indications and Usage (1.1, 1.2)].

Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Aerobic bacteria:

Gram-positive bacteria:

Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates)
Staphylococcus haemolyticus
Staphylococcus lugdunensis
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus)
Enterococcus faecalis

Gram-negative bacteria:

Escherichia coli
Klebsiella pneumoniae
Enterobacter cloacae
Pseudomonas aeruginosa

Community-Acquired Bacterial Pneumonia (CABP)

Aerobic bacteria:

Gram-positive bacteria:

Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible isolates only)

Gram-negative bacteria:

Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Pseudomonas aeruginosa

Other microorganisms:

Chlamydia pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint of delafloxacin against isolates of similar genus or organism group. However, the efficacy of BAXDELA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria:

Gram-positive bacteria:

Streptococcus dysgalactiae

Gram-negative bacteria:

Enterobacter aerogenes
Klebsiella oxytoca
Proteus mirabilis
Moraxella catarrhalis

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Long-term carcinogenicity studies have not been conducted with BAXDELA.

Delafloxacin was not mutagenic in a bacterial reverse mutation (Ames) assay, and was not clastogenic in a mouse bone marrow micronucleus test at ≥15 times the estimated human plasma exposure based on AUC. In an in vitro clastogenicity assay using isolated human lymphocytes, delafloxacin was negative in short incubations (~3 hours) and, at high cytotoxic concentrations (>1.0 mM), was positive in a long incubation (~19 hours).

Delafloxacin did not affect the fertility of male and female rats up to the highest intravenous dose tested (120 mg/kg/day); female rats were dosed 2 weeks prior to mating and through gestation day 7 and male rats were treated for 28 days prior to mating and beyond for a total of 58-59 days. AUC in male and female (non-pregnant and pregnant) rats at 120 mg/kg/day delafloxacin intravenous was estimated to be approximately 5 times the estimated human plasma exposure based on AUC in separate intravenous toxicology studies in rats, one of which was a 2-week study that used a different vehicle for delafloxacin than in the fertility study, and another was an 8-day study in nonpregnant and pregnant (gestation day 13) rats that used the same vehicle for delafloxacin as in the fertility study.

Fluoroquinolone antibacterials are associated with degenerative changes in articular cartilage and arthropathy in skeletally immature animals. In a toxicology study of the formulated tablet in dogs, the femoral head of one of three high dose (480 mg/kg/day) females had minimal focal degeneration of the superficial articular cartilage and a small focal cleft in the articular cartilage. No other joints were examined.

14.1 Acute Bacterial Skin and Skin Structure Infections

A total of 1510 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial 1 compared BAXDELA 300 mg via intravenous infusion every 12 hours to comparator. In Trial 2, patients received BAXDELA 300 mg via intravenous infusion every 12 hours for 6 doses then made a mandatory switch to oral BAXDELA 450 mg every 12 hours. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures.

In Trial 1, 331 patients with ABSSSI were randomized to BAXDELA and 329 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (39%), wound infection (35%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion as measured by digital planimetry was 307 cm². The average age of patients was 46 years (range 18 to 94 years). Patients were predominately male (63%) and white (91%); 32% had BMI ≥30 kg/m². The population studied in Trial 1 included a distribution of patients with associated comorbidities such as hypertension (21%), diabetes (9%), and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 55% of patients. Bacteremia was documented at baseline in 2% of patients.

In Trial 2, 423 patients were randomized to BAXDELA and 427 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (48%), wound infection (26%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion, as measured by digital planimetry, was 353 cm². The average age of patients was 51 years (range 18 to 93 years). Patients were predominately male (63%) and white (83%); 50% had a BMI ≥30 kg/m². The population studied in Trial 2 included a distribution of patients with associated comorbidities such as hypertension (31%), diabetes (13%) and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 30% of patients. Bacteremia was documented at baseline in 2% of patients.

In both trials, objective clinical response at 48 to 72 hours post initiation of treatment was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema. Table 7 summarizes the objective clinical response rates in both of these trials.

Table 7. Clinical Response at 48–72 hours* in the ITT Population with ABSSSI in Trial 1 and Trial 2:

CI = Confidence Interval; ITT = Intent To Treat and includes all randomized patients
* Objective clinical response was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema at 4 8 to 72 hours after initiation of treatment without any reasons for failure (less than 20% reduction in lesion size, administration of rescue antibacterial therapy, use of another antibacterial or surgical procedure to treat for lack of efficacy, or death). Missing patients were treated as failures.
^† Treatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification.

In both trials, an investigator assessment of response was made at Follow-up (Day 14 ± 1) in the ITT and CE populations. Success was defined as “cure + improved,” where patients had complete or near resolution of signs and symptoms, with no further antibacterial needed. The success rates in the ITT and CE populations are shown in Table 8.

Table 8. Investigator-Assessed Success at the Follow-up Visit in ABSSSI —ITT Population and CE Population in Trial 1 and 2:

CI = Confidence Interval; ITT = Intent To Treat and includes all randomized patients; CE = Clinically Evaluable consisted of all ITT patients who had a diagnosis of ABSSSI, received at least 80% of expected doses of study drug, did not have any protocol deviations that would affect the assessment of efficacy and had investigator assessment at the Follow-Up Visit.

Six delafloxacin patients had baseline S. aureus bacteremia with ABSSSI. Five of these 6 patients (83.3%) were clinical responders at 48 to 72 hours and 5/6 (83.3%) were considered clinical success for ABSSSI at Day 14 ± 1. Two delafloxacin patients had baseline Gram-negative bacteremia (K. pneumoniae and P. aeruginosa), and both were clinical responders and successes.

The investigator assessments of clinical success rates were also similar between treatment groups at Late Follow-up (LFU, day 21-28).

Objective clinical response and investigator-assessed success by baseline pathogens from the primary infection site or blood cultures for the microbiological ITT (MITT) patient population pooled across Trial 1 and Trial 2 are presented in Table 9.

Table 9. Outcomes by Baseline Pathogen (Pooled across Trial 1 and Trial 2; MITT* Population):

* Microbiological ITT (MITT) consists of all randomized patients who had a baseline pathogen identified that is known to cause ABSSSI.
^† Objective clinical response was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema at 4 8 to 72 hours after initiation of treatment.
^‡ Investigator-assessed success was defined as complete or near resolution of signs and symptoms, with no further antibacterial needed at Follow-up Visit (Day14 ± 1).
^§ Discrepancy in the total numbers is due to the multiple subjects having both MRSA and MSSA isolates.

14.2 Community-Acquired Bacterial Pneumonia

A total of 859 adults with CABP were randomized in a multicenter, multinational, double-blind, double-dummy, noninferiority trial comparing BAXDELA to moxifloxacin (Trial 3, NCT 02679573). In this trial, BAXDELA for injection 300 mg was administered intravenously (IV) every 12 hours with an option to switch to BAXDELA tablet 450 mg orally every 12 hours. Moxifloxacin 400 mg was administered IV every 24 hours with an option to switch to moxifloxacin tablet 400 mg orally every 24 hours. Switch to oral treatment was allowed after a minimum of 3 days of IV dosing. Total treatment duration was 5 to 10 days. In the moxifloxacin arm, the investigator could switch patients to linezolid 600 mg every 12 hours if methicillin-resistant Staphylococcus aureus (MRSA) was confirmed.

A total of 431 patients were randomized to BAXDELA and 428 to moxifloxacin. Patient demographic and baseline characteristics were balanced between the treatment arms. In this trial, 12.9% of patients were in PORT Risk Class II, 60.3% were in PORT Risk Class III, 25.4% were in PORT Risk Class IV, and 1.4% were in PORT Risk Class V. The average age of patients was 60 years (range 18 to 93 years). Patients were predominantly male (58.7%) and white (91.5%); average BMI was 26.9 kg/m². Associated comorbidities included pre-existing pulmonary disease (13.6%), cardiac disease (23.9%), diabetes (15.3%), and mild to severe renal impairment (76.9%). Bacteremia was documented at baseline in 1.5% of patients. The majority of sites were in Eastern Europe, which accounted for 82.8% of enrollment. One subject (0.2%) was enrolled in the BAXDELA arm and 5 (1.2%) in the moxifloxacin arm from the United States.

Early clinical response (ECR) at 72-120 hours after the first dose was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, and without use of additional antimicrobial therapy for treatment of the current CABP infection due to lack of efficacy.

Table 10. Early Clinical Response* at 72 to 120 hours in the ITT Population with CABP (Trial 3):

CI = Confidence Interval; ITT = Intent To Treat includes all randomized patients
* Early Clinical Response (ECR) at 72-120 hours after the first dose, was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, and without use of additional antimicrobial therapy for treatment of the current CABP infection due to lack of efficacy.
^† Treatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification.

Clinical response was also assessed by the investigator at the test of cure (TOC) visit and defined as survival with resolution or near resolution of the symptoms of CABP present at study entry, and no use of additional antimicrobial therapy for the current CABP infection, and no new symptoms associated with the current CABP infection.

Clinical response rates at the TOC visit for the ITT and Clinically Evaluable (CE) populations are presented in Table 11.

Table 11. Investigator-Assessed Success at the TOC Visit in CABP —ITT Population and CE Population in Trial 3:

CI = Confidence Interval; ITT = Intent To Treat and includes all randomized patients; CE = Clinically Evaluable
Clinically Evaluable consisted of all ITT patients who had evidence of acute CABP, received at least 80% of expected doses of the correct study drug, did not receive any concomitant, systemic antibacterial therapy except for lack of efficacy, and did not have any protocol deviations that would affect the assessment of efficacy.
* Treatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification.
^† Success was survival with resolution or near resolution of the symptoms of CABP present at study entry, and no use of additional antimicrobial therapy for the current infection, and no new symptoms associated with the current CABP infection.

Early clinical response and investigator-assessed clinical response at the TOC visit is presented in Table 12 by baseline pathogen for the Microbiological ITT (MITT) population which comprised all randomized patients who had a baseline pathogen identified that is known to cause CABP.

Table 12. Outcome by Baseline Pathogen (CABP, Trial 3, MITT Population)*:

* Excludes patients with baseline pathogens resistant or non-susceptible to moxifloxacin.
^† Early Clinical Response (ECR) at 72-120 hours after the first dose, was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, and without use of additional antimicrobial therapy for treatment of the current CABP infection due to lack of efficacy.
^‡ Investigator-assessed success was defined as survival with resolution or near resolution of the symptoms of CABP present at study entry, and no use of additional antimicrobial therapy for the current infection, and no new symptoms associated with the current CABP infection at Test of Cure (TOC) visit at (5 to 10 days after last dose of study drug).