Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: CIPLA MEDPRO (PTY) LTD, Building 9, Parc du Cap, Mispel Street, Bellville, 7530, RSA
A 20.2.8 – Antimicrobial (Chemotherapeutic) Medicine. Other than antibiotics.
Antiviral Medicine.
Dolutegravir inhibits HIV integrase by binding to the integrase active sites and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. In vitro, dolutegravir dissociates slowly from the active site of the wild type integrase-DNA complex (t1/2 71 hours).
Isolation from wild type HIV-1: Viruses highly resistant to dolutegravir have not been observed during HIV-1 passage. During wild type HIV-1 passage in the presence of dolutegravir integrase substitution observed were S153Y and S153F with FCs ≤ 4,1 for strain IIIB, or E92Q with FC = 3,1 and G193E with FC = 3,2 for strain NL432. Additional passage of wildtype subtype B, C and A/G viruses in the presence of dolutegravir selected for R263K, G118R, and S153T.
Anti-HIV activity Against Resistant Strains: Reverse Transcriptase Inhibitor- and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent potency against 2 non-nucleoside (NN)-RTI-resistant, 3 nucleoside (N)-RTI-resistant and 2 PI-resistant HIV-1 mutant clones (1 triple and 1 sextuple) compared to the wild-type strain. Integrase Inhibitor-Resistant HIV-1 Strains: Dolutegravir showed anti-HIV activity (susceptibility) with FC < 5 against 27 of 28 integrase inhibitor-resistant mutant viruses with single substitutions including T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R, and N155H. Integrase Inhibitor-Resistant HIV-2 Strains: Site directed mutant HIV-2 viruses were constructed based on subjects infected with HIV-2 and treated with raltegravir who showed virologic failure. Overall, the HIV-2 FCs observed were similar to HIV-1 FCs observed for similar pathway mutations.
Integrase inhibitor naïve patients: No integrase inhibitor (INI) resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment – naïve studies.
The effect of dolutegravir on serum creatinine clearance (CrCl), glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using para-aminohippurate (PAH) as the probe was evaluated. A small decrease of 10–14% in mean serum creatinine clearance (CrCl) was observed with dolutegravir within the first week of treatment. Dolutegravir has no significant effect on glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF). In vitro studies suggest that the increases in creatinine observed in clinical studies are due to the non-pathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), is a selective inhibitor of HIV-1 and HIV-2 replication in-vitro.
Lamivudine is metabolised intracellularly to the 5'-triphosphate which has intracellular half-life of 16 – 19 hours.
Lamivudine 5'triphosphate is a weak inhibitor of the RNA and DNA-dependent activities of HIV reverse transcriptase, its mode of action is a chain terminator of HIV reverse transcription.
Reduced in vitro sensitivity to lamivudine has been reported for HIV isolates from patients who have received lamivudine therapy.
Lamivudine-resistant HIV-1 mutants are cross-resistant to didanosine and zalcitabine. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content.
Tenofovir disoproxil fumarate, is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate and is converted in vivo to tenofovir. It is a nucleoside reverse transcriptase inhibitor.
Tenofovir is phosphorylated by cellular enzymes to form tenofovir diphosphate.
Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase Ɣ.
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro and a K65R mutation in reverse transcriptase have been selected in vitro and, in some patients, treated with tenofovir in combination with certain antiretroviral medicines. In treatment naïve patients treated with tenofovir + lamivudine + efavirenz, viral isolates from 17% patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-experienced patients, some of the tenofovir-treated patients with virologic failure through week 96 showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 reverse transcriptase gene resulting in the K65R amino acid substitution.
Cross-resistance among certain reverse transcriptase inhibitors has been recognised. The K65R mutation can also be selected by abacavir, didanosine, or zalcitabine and results in reduced susceptibility to these medicines plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil fumarate should be avoided in antiretroviral experienced patients with strains harbouring the K65R mutation. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate.
The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV1 has been assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0,04 µM – 8,5 µM. In medicine combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC50 values ranged from 0,5 µM to 2,2 µM). The IC50 values of tenofovir against HIV-2 ranged from 1,6 µM to 4,9 µM.
Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is between low to moderate. In Phase 1 studies in healthy subjects, between-subjects CVb % for AUC and Cmax ranged from–20 to 40% and CT from 30 to 56% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subjects variability (CVw %) is lower than between-subject variability.
Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours post-dose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1,2 to 1,5. Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.
Dolutegravir may be administered with or without food. Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate and high fat meals increased dolutegravir AUC(0–∞) by 33%, 41 % and 66 , increased Cmax by 46, 52% and 67% and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. These increases are not clinically significant.
Dolutegravir is highly bound (greater than or equal to 98,9 %) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17,4 L based on a population pharmacokinetic analysis. Binding of dolutegravir to plasma proteins is independent of concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0,441 to 0,535 indicating minimal association of radioactivity with blood cellular components. Free fraction of dolutegravir in plasma is estimated at approximately 0,2 to 1,1 % in healthy subjects with moderate hepatic impairment, and 0,8 to 1,0 % in subjects with severe renal impairment and 0,5 % in HIV-1 infected patients. Dolutegravir is present in cerebrospinal fluid (CSF). In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13,2 ng per mL (range: 3,74 ng per mL to 18,3 ng per mL) 2 to 6 hours post-dose after 16 weeks of treatment. The clinical relevance of this finding has not been established.
Dolutegravir is primarily metabolised via UGT1A1 with some contribution from CYP3A. Dolutegravir is the predominant circulating compound in plasma. After a single oral dose of [14C] dolutegravir, 53 % of the total oral dose was excreted unchanged in feces. It is unknown if all or part of this is due to unabsorbed medicine or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-one percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18,9 % of total dose), N-dealkylation metabolite (3,6 % of total dose) and a metabolite formed by oxidation at the benzylic carbon (3,0 % of total dose). Renal elimination of unchanged drug was low (less than 1 % of the dose).
Dolutegravir has a terminal half-life of ~14 hours and an apparent oral clearance (CL/F) of 1,0 L per hour based on population pharmacokinetic analyses.
The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to 18 years of age) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure comparable to that observed in adults who receive dolutegravir 50 mg once daily.
Table 1. Adolescent pharmacokinetic parameters:
Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed there is no clinically relevant effect of age on dolutegravir exposure.
Pharmacokinetic data for dolutegravir in subjects of > 65 years old are limited.
Renal clearance of unchanged medicine is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CLcr < 30 mL/min) and matching healthy subjects were observed, AUC, Cmax, and C24 of dolutegravir were decreased by 40%, 23% and 43% respectively, compared with those in matched healthy subjects. No dosage adjustment is necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.
Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh category B score 7 to 9) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the two groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
There is no evidence that common polymorphisms in metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT 1A1 (n=41). Polymorphisms in CYP3A4, CYP3A5 and NR1I2 are not associated with differences in the pharmacokinetics of dolutegravir.
Population pharmacokinetic analysis indicate that Hepatitis C virus co-infection has no clinically relevant effect on the exposure to dolutegravir. There are limited data on patients with Hepatitis B co-infection.
Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. After oral administration of 2 mg per kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1,5 ± 0,5 µg per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0,25 to 10 mg per kg. The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1,50 following 15 days of oral administration of 2 mg per kg twice daily. The mean time (Tmax) to maximum serum concentration (Cmax) is about an hour.
Lamivudine tablets and oral solution may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3,2 ± 1,3 hours) compared with the fasted state (Tmax: 0,9 ± 0,3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states.
The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1,3 ± 0,4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.
Binding of lamivudine to human plasma proteins is low (less than 36%). In vitro studies showed that over the concentration range of 0,1 to 100 µg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5 % of an oral dose after 12 hours). Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by CYP450 enzymes.
The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199,7 ± 56,9 mL per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280,4 ± 75,2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.
In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398,5 ± 69,1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0,25 to 10 mg per kg.
No dose adjustment is needed when co-administered with food as lamivudine bioavailability is not altered, although a delay in Tmax and reduction in Cmax have been observed. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin. Lamivudine elimination will be affected by renal impairment.
Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary. The likelihood of adverse drug interactions with lamivudine is low due to the limited metabolism and plasma protein binding and almost complete renal clearance.
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patients also have renal impairment. Administration of cotrimoxazole with the 3TC/zidovudine combination in patients with renal impairment should be carefully assessed. Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2 – 4 hours after oral administration is approximately 0,12. The true extent of penetration or relationship with any clinical efficacy is unknown.
In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability (approximately 55–65%) was reduced in paediatric patients below 12 years of age. In addition, systemic clearance values were greater in younger paediatric patients and decreased with age approaching adult values around 12 years of age. Recent findings indicate that exposure in children 2 to <6 years of age may be reduced by about 30 % compared with other pharmacokinetic data for patients <3 months of age. In neonates one week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely due to immature renal function and variable absorption.
Following oral administration, lamivudine pharmacokinetics in late-pregnancy were similar to non-pregnant adults. Administration of lamivudine in animal toxicity studies at very high doses was not associated with any major organ toxicity. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia. Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity in an in vitro cytogenic assay.
Lamivudine was not genotoxic in vivo at doses that gave plasma concentrations around 30 – 40 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment. There is as yet no information on the tumorigenic risk in animals, and therefore any potential risk to humans must be balanced against the expected benefits of treatment.
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients is approximately 25 %. Following oral administration of a single 300 mg dose of tenofovir disoproxil fumarate to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1,0 ± 0,4 hrs (mean ± SD), and Cmax and AUC values are 0,30 ± 0,09 μg/mL and 2,29 ± 0,69 μg•hr/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over a dose range of 75 to 600 mg and are not affected by repeated dosing.
In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 113,4 g applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
Administration of tenofovir following a high-fat meal (˜700 to 1000 kcal containing 40% to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40 % and an increase in Cmax of approximately 14 %. However, administration of tenofovir with a light meal does not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the medicine. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0,33 ± 0,12 μg/mL and 3,32 ± 1,37 μg•hr/mL following multiple doses of tenofovir disoproxil 300 mg once daily in the fed state, when meal content was not controlled.
In vitro binding of tenofovir to human plasma proteins is less than 0,7% and 7,2%, respectively over the tenofovir concentration range of 0,01 – 25 µg/mL. The volume of distribution at steady-state is 1,3 ± 0,6 L/kg and 1,2 ± 0,4 L/kg, following intravenous administration of tenofovir 1,0 mg/kg and 3,0 mg/kg.
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes. Following IV administration of tenofovir, approximately 70 – 80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (>65 years).
Tenofovir pharmacokinetics after a 300 mg single dose have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. Change in tenofovir dosing is not required in patients with hepatic impairment.
Tenofovir pharmacokinetics are altered in patients with renal impairment. In patients with creatinine clearance <50 ml/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax and AUC0-∞ of tenofovir were increase. It is recommended that the dosing interval for tenofovir be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (see 4.2 Posology and method of administration). Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir, a four-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.
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