Loading

Clinical pharmacology of lamivudine administered alone, or co-administered with other antiviral drugs, in infants and children

Research Article | Open Access

  • 1. Associate Professorof Pharmacology, Italy
+ Show More - Show Less
Corresponding Authors
Gian Maria Pacifici, Associate Professor of Pharmacology,via Sant’Andrea 32,56126, Pisa,Italy
Abstract

Lamivudine is a cytidine analogue reverse transcriptase inhibitor that is active against HIV-1, HIV-2, and HBV; it is approved for HIV in adults and in children aged 3 months or older. Lamivudine enter cells by passive diffusion and is phosphorylated to lamivudine 5’-triphosphate which is the active anabolite. Lamivudine is administered orally, its oral bioavailability is 86%, and lamivudine is primarily excreted unchanged in the urine. Lamivudine may be administered alone but in most cases it is co-administered with other antiviral drugs. The oral dose of lamivudine is 4 mg/kg twice-daily in infants, and in children it is computed according to the child age and body-weight and the maximum dose is 300 mg once-daily. Lamivudine co-administered with antiviral drugs has been found efficacy and safe in infants and children with HIV-infection and lamivudine prevents the transmission of hepatitis B virus from mother-to-infant. Lamivudine elimination half-life is about 6 hours in infants and about 4 hours in infants and children. The prophylaxis and treatment with lamivudine have been studied in infants and children. The prophylaxis and treatment often consist in lamivudine co-administered with other antiviral drugs such as nevirapine, lopinavir/ritonavir or zidovudine. Lamivudine freely crosses the human placenta and freely migrates into the breast-milk. The aim of this study is to review the lamivudine dosing, efficacy, safety, prevention of mother-toinfant transmission of hepatitis B virus, pharmacokinetics, interaction with drugs, prophylaxis, and treatment in infants and children, the transfer across the human placenta and the migration into the breast-milk

Keywords

• lamivudine • Dosing • Efficacy • Safety • Pharmacokinetics • Prophylaxis • Treatment • Placenta • Breast-milk • Infants and children

INTRODUCTION

Lamivudine (3TC) is a cytidine analogue reverse transcriptase inhibitor that is active against HIV-1, HIV-2 (HIV: human immunodeficiency virus), and HBV (hepatitis B virus). Lamivudine is approved for HIV in adults and children aged 3 months or older. Lamivudine has been effective in combination with other antiretroviral drugs in both treatment-naïve and -experienced patients and is a common component of therapy, given its safety, convenience, and efficacy. Lamivudine is also approved for treatment of chronic HBV infection [1].

Mechanism of action of lamivudine

Lamivudine enter cells by passive diffusion and is sequentially phosphorylated to lamivudine 5’-triphosphate which is the active anabolite. Lamivudine has low affinity for human DNA polymerase, explaining its low toxicity to the host. Highlevel resistance to lamivudine occurs with single-amino-acid substitutions, M184V or M184I. These mutations can reduce invitro sensitivity to lamivudine as much as 1,000-fold. The M184V mutation restores the susceptibility in zidovudine-resistant HIV harbouring the K65R mutation. The effect may contribute to the sustained virological benefits of zidovudine and lamivudine combination therapy [1].

Absorption distribution metabolism and excretion of lamivudine

The oral bioavailability of lamivudine is 86% and the food does not affect the bioavailability of lamivudine. In adults, the elimination half-life is 1.1 hours and that of lamivudine 5’-triphosphate is 12 hours. Lamivudine binds to plasma protein to < 35%, is metabolized at a rate < 36% and the renal excretion of lamivudine is 71%. Lamivudine is excreted primarily unchanged in the urine; dose adjustment is recommended in patients with a creatinine clearance < 50 ml/min. Lamivudine freely crosses the placenta and it is transferred to the foetal circulation [1].

Literature search

The literature search was performed electronically using PubMed database as search engine and the following key words were used: “lamivudine dosing infants, children“, lamivudine efficacy, safety infants, children”, “lamivudine pharmacokinetics infants, children”, “lamivudine drug interactions”, “lamivudine prophylaxis infants, children”, “lamivudine treatment infants, children”, “lamivudine placental transfer”, and “lamivudine migration into the breast-milk”. In addition, the books: The Pharmacological Basis of Therapeutics [1], Neonatal Formulary [2], NEOFAX® by Young and Mangum [3], and The British National Formulary for Children [4] were consulted.

 

RESULTS

Administration schedules of lamivudine to infants and children

Oral administration to infants [2]

Infants: Give: 4 mg/kg twice-daily alone or combined with two or more antiviral drugs. In the rare situations where treatment is called for the first month of life give 2 mg/kg twicedaily.

Prevention of mother-to-infant HIV transmission in infants born to HIV-infected women who have had received no therapy during pregnancy (has received intrapartum therapy only) in combination with zidovudine. The use of lamivudine with zidovudine for 7 days postpartum is an alternative regimen according to WHO guidelines. The decision to use combination infant antiretroviral prophylaxis, or the treatment of infected infants with combination antiretroviral therapy, should be done in consultation with a paediatric infectious disease expert [3].

Oral treatment to children [4]

Oral treatment of HIV-infection in combination with other antiretroviral drugs using Epivir® oral solution

Children aged 1 to 2 months. Give: 4 mg/kg twice-daily.

Children aged 3 months to 11 years with body-weight up to 14 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively give: 8 mg/kg once-daily (maximum dose = 300 mg).

Children aged 3 months to 11 years with body-weight of 14 to 20 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg), alternatively 75 mg twice-daily, alternatively 150 mg once-daily.

Children aged 3 months to 11 years with body-weight of 21 to 29 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg), alternatively 75 mg/kg daily and the dose should be taken in the morning and 150 mg should be taken in the evening, alternatively the dose is 225 mg once-daily.

Children aged 3 months to 11 years with body-weight ≥ 30 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg), alternatively 300 mg once-daily, alternatively 150 mg twicedaily

Children aged 12 to 17 years. Give: 150 mg twice-daily, alternatively 300 mg once-daily

. Oral treatment of HIV-infection in combination with other antiviral drugs using Epivir® tablets

Children aged 1 to 2 months. Give: 4 mg/kg twice-daily.

Children aged 3 months to 11 years with body-weight up to 14 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg).

Children aged 3 months to 11 years with body-weight of 14 to 20 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg), alternatively 75 mg twice-daily, alternatively 150 mg once-daily

Children aged 3 months with body-weight of 21 to 29 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg), alternatively 75 mg daily and the dose should be taken in the morning and 150 mg should be taken in the evening, alternatively 225 mg once-daily

Children aged 3 to 11 years with body-weight ≥ 30 kg. Give: 4 mg/kg twice-daily (maximum dose = 150 mg), alternatively 8 mg/kg once-daily (maximum dose = 300 mg), alternatively 150mg twice-daily, alternatively 300 mg once-daily.

Children aged 12 to 17 years. Give: 150 mg twice-daily, alternatively 300 mg once-daily.

Oral treatment of chronic hepatitis B infection either with compensated liver disease (with evidence of viral replication and history of active liver inflammation or fibrosis) when the firstline treatments cannot be used, or (in combination with another antiviral drug without cross-resistance to lamivudine) with decompensated liver cirrhosis using Zeffix®.

Children aged 2 to 11 years. Give: 3 mg/kg once-daily (maximum dose = 100 mg), children receiving lamivudine for concomitant HIV-infection should continue to receive lamivudine in a dose appropriate for HIV-infection

Children aged 12 to 17 years. Give: 100 mg once-daily, children receiving lamivudine for concomitant HIV-infection should continue to receive lamivudine in a dose appropriate for HIV-infection.

Epivir® oral solution and tablets and Zeffix® are British formulations

Efficacy and safety of lamivudine co-administered with other antiviral drugs in infants and children

ntiviral drugs in infants and children Treatment with nevirapine plus zidovudine and lamivudine started in the first week of life is efficacy and safe, even when the trough concentration of nevirapine is below the target value. Transient HIV increases occur following transmission to lopinavir/ritonavir but at 12 and 24 weeks of treatment most infants achieved and maintained viral suppression [5]. Lamivudine co-administered with zidovudine is safe and effective in preventing maternal-to-infant HIV transmission [6]

Zidovudine plus lamivudine, lopinavir/ritonavir was found efficacy and safe in children with HIV-infection [7].

Efficacy and safety of lamivudine administered alone or co-administered with other antiviral drugs in preventing the mother-to-infant transmission of hepatitis B virus

Lamivudine treatment of highly hepatitis B infection in pregnant women decreases the perinatal transmission of hepatitis B virus and lowers the infection caused by this virus in newborn infants [8]. Lamivudine prevents the maternalto-infant hepatitis B virus transmission and reduces the complications caused by this virus in pregnant women and their newborn infants [9]. Continuous antiviral therapy with lamivudine from preconception to entire pregnancy is effective and safe for treatment of chronic hepatitis B virus in mothers and their newborn infants [10]. Lamivudine is efficacy and safe in preventing the transmission of hepatitis B virus from the mothers to their newborn infants [11]. Lamivudine treatment in hepatitis B virus carrier-mothers from 28 week of gestation interrupts the mother-to-infant transmission of hepatitis B virus. Lamivudine is safe and more efficient than hepatitis B immunoglobulin in interrupting mother-to-infant transmission of hepatitis B virus [12]. Lamivudine in hepatitis B virus carrier-mothers with high degree of infectiousness in late pregnancy effectively prevents hepatitis B virus intrauterine infection and the maternal-to-infant transmission [13]. Lamivudine therapy is efficacious and safe in infants with chronic hepatitis B [14]. Lamivudine and telbivudine treatment initiated in the third trimester of pregnancy for mothers with hepatitis B DNA > 1*106 IU/ml is efficacy and safe in preventing the transmission of hepatitis B virus from mothers to their newborn infants [15].

Both lamivudine and tenofovir exhibited a high efficacy in preventing the transmission of the hepatitis B virus from the mothers to their newborn infants [16].

Pharmacokinetics of lamivudine in infants

Mirochnick et al. [17] studied the pharmacokinetics of lamivudine in 26 infants during the first two weeks of life. Fourteen infants were aged 4 to 7 days and 12 infants were aged 10 to 14 days. The median gestational age is 39 weeks (range, 34 to 42) and body-weight is 3,105 grams (range, 1,775 to 3,900). The median HIV viral load is 8,622 copies/ml (range, 224 to 53,773), and a median CD4 cell count is 704 cells/mm3 (range, 143 to 1,711). Infants were treated with nelfinavir at a median dose of 58.8 mg/kg (range, 48.7 to 79.0) and lamivudine at a median dose of 2.0 mg/kg (range, 1.5 to 3.2). Nelfinavir and lamivudine were administered orally twice-daily. [Table 1]

This table shows that the elimination half-life is the only pharmacokinetic parameter that differs in the two groups of infants and it is shorter in infants aged 10 to 14 days than in infants aged 4 to 7 days.

Pharmacokinetics of lamivudine in infants and children

Tremoulet et al. [18] investigated the pharmacokinetics of lamivudine in 99 HIV-exposed infants and children aged 56+163 days (range, 3 to 757) and weighing 4.2+2.7 kg (range, 2.1 to 16.2). Lamivudine was administered orally at a dose of 2 to 4 mg/ kg twice-daily. Further information about lamivudine dosing is included in [Table 2]

 

Table 1. Pharmacokinetic parameters which are obtained in 13 infants aged 4 to 7 days and in 12 infants aged 10 to 14 days. Figures are the median and (range), by Mirochnick et al [17]

Parameter Age 4 to 7 days (N = 13 Age 10 to 14 days (N = 12) Combined age groups (N = 25)
Tmax (h) 2.8 (1 – 4) 2.5 (1 – 4) 2.5 (1 – 4)
Peak concentration (µg/ml) 1.08 (0.38 – 2.01 1.27 (0.38 – 2.17) 1.24 (0.38 – 2.17)
Concentration at 12 hours (µg/ml) 0.31 (bql – 0.74) 0.22 (bql – 0.62) 0.23 (bql – 0.74
AUC0-12 h (µg*h/ml) 7.0 (2.9 – 15.6) 7.9 (2.7 – 14.0) 7.8 (2.4 – 15.6)
Total body clearance/F (L/h/kg) 0.27 (0.11 – 0.70) 0.27 (0.14 – 0.74) 0.27 (0.11 – 0.74)
Elimination half-life (h) 5.3 (3.3 – 10.5) 3.9 (3.1 – 6.3)* 4.3 (3.1 – 10.5)

Tmax = time to reach the peak concentration. F = oral bioavailability. bql = below quantification limit. *P-value < 0.05 (Student t test for unpaired data).

This table shows that the total body clearance, corrected for the oral bioavailability, is greater in children than in infants. The distribution volume is not different in infants and children and it is greater than the water volume. The elimination half-life is longer in infants than in infants and children, the AUC is similar in infants and children and there is a wide interindividual variability in the pharmacokinetic parameters

Pharmacokinetics of lamivudine administered alone or co-administered with zidovudine in newborn infants

nfants Moodley et al. [19] explored the pharmacokinetics of lamivudine administered alone or co-administered with zidovudine in twenty pregnant women infected by HIV-1 and in their offspring. Ten women received 4 mg/kg of lamivudine and 10 women were treated with lamivudine at a dose of 150 mg plus zidovudine at a dose of 300 mg and both drugs were administered orally twice-daily during the first week before delivery and intrapartum. Ten newborn infants received lamivudine at a dose of 4 mg/kg twice-daily and 10 newborn infants received this dose of lamivudine plus 2 mg/kg zidovudine 4 times-daily orally. Lamivudine and zidovudine were administered orally. [Table 3]

This table shows that zidovudine causes a modest reduction of AUC and peak concentration of lamivudine.

Bergshoeff et al. [20] studied the pharmacokinetics of lamivudine in 19 HIV-1-infected children aged 2 to 13 years who were clustered into two groups according to the age. Then children of group A were aged ≥ 2 to 6 years, and 9 children of group B were aged > 6 to 13 years. The oral dose of lamivudine was 4 mg/kg twice-daily or 8 mg/kg once-daily (Table 4).

This table shows that the minimum concentration of lamivudine is the only pharmacokinetic parameter which is different in the two groups of children

Interaction of lamivudine with drugs

Lamivudine dolutegravir interaction is particularly relevant because increase the risk of toxicity in patients with HIV [21]

Lamivudine is a substrate of renal drug transporters OCT2, MATE1, and MATE2-K and concomitant administration of drugs

 

Table 2. Comparison of lamivudine pharmacokinetic parameters in HIV-infected infants and children. Figures are the median and (interquartile range), by Tremoulet et al. [18].

Age group (sample size) Oral dose (twice-daily] Pharmacokinetic parameter: median and 95% confidence interval      
    TBC/F (L/h/kg) DV/F (L/kg) *Half-life (h) AUC0-12 h (µg*h/ml)
3-26 days (N = 40) 2 mg/kg 0.37 (0.25 – 0.48) 3.12 (2.29 – 3.96) 6.2 (4.6 – 7.8) 6.0 (4.0 – 8.0)
1 day (N = 16) 2 mg/kg 0.19 (0.14 – 026) NA 6.2 (5.3 – 8.0) 9.8 (7.6 – 14.1)
7 days (N = 16) 2 mg/kg 0.32 (0.26 – 40) NA 7.9 (7.0 – 9.0) 6.3 (5.0 – 7.8)
29 days-3 years (N = 59 4 mg/kg 0.66 (0.46 – 0.86) 3.44 (2.53 – 4.35) 3.8 (2.8 – 4.8) 6.8 (3.9 – 9.7)

TBC = total body clearance. F = oral bioavailability. DV = distribution volume. NA = not available. *Elimination half-life.

 

Table 3. Pharmacokinetic parameters which are obtained in 10 newborn infants who received 4 mg/kg lamivudine twice-daily and in 10 newborn infants who received this dose of lamivudine plus 2 mg/kg zidovudine 4 times-daily. Figures are the geometric least squire (95% confidence interval), by Moodley et al. [19].

  Lamivudine    
Parameter Monotherapy With zidovudine Comparison
AUC? (µg/h/ml 16.88 (13.4 – 21.3) 15.63 (12.4 – 19.7) 1.07 (0.85 – 1.33)
Peak conc. (µg/ml) 1.97 (1.6 – 2.3) 1.69 (1.3 – 2.2) 1.17 (0.91 – 1.49)
Tmax (h) 3.0 (1.0 – 8.0) 3.0 (1.0 – 3.0) ....
TBC/F (L/h) 1.1 (0.9 – 1.3) 1.2 (0.8 – 1.6) 0.90 (0.71 – 1.14)
Elimination half-life (h) 6.0 (5.1 – 6.8) 6.6 (5.3 – 7.9) 0.90 (0.76 – 1.07)

AUC? = ? is the dosing interval. TBC = total body clearance. F = oral bioavailability. Tmax = the time to reach the lamivudine peak concentration

that inhibit these transporters decrease the renal clearance of lamivudine [22]. Trimethoprim-sulfamethoxazole increases the lamivudine plasma concentrations by 43% [23].

Prophylaxis with lamivudine in infants and children

The prophylaxis of infants infected by HIV-1 with lopinavir/ ritonavir is not superior to that with lamivudine and both drugs led to very low rates of HIV-1 postnatal transmission for up to 50 weeks of breastfeeding [24]. The prophylaxis with lopinavir/ ritonavir or with lamivudine prevents the HIV-1-infection in infants [25]. The prophylaxis with zidovudine/lamivudine or with didanosine prevents HIV-1-infection in children [26]. Zidovudine plus lamivudine and lopinavir/ritonavir prevents the HIV-1-infection in children [27]

Treatment with lamivudine in infants and children

Among infants with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting in zidovudine and lamivudine plus ritonavir/lopinavir results in better outcomes than does the treatment with zidovudine and lamivudine plus nevirapine [28]. Less weight gain is observed in infants given lopinavir/ ritonavir than those given lamivudine, which is indicative of a persistent effect that could have long-term deleterious effects [29]. Reduction of viremia by lamivudine therapy in the last month of pregnancy is an effective and safe measure to reduce the risk of hepatitis B virus in newborn infants [30]. Children exposed to lopinavir/ritonavir and lamivudine at birth for 1year have comparable growth and neuropsychological outcomes without evidence of long-term side-effects [31]. Lamivudine monotherapy should be administered temporarily while efforts to improve adherence are implemented. Lamivudine should not be considered a default option in children with virological failure [32]. One year lamivudine therapy for children with chronic hepatitis B virus is effective and well tolerated treatment [33]

 

Table 4. Lamivudine pharmacokinetic parameters which are obtained in two groups of children. Figures are the geometric mean, (90% confidence interval), and P-values, by Bergshoeff et al. [20].

  Lamivudine 4 mg/kg twice-daily     Lamivudine 8 mg/kg once-daily

 

   
Parameter 10 Children of group A 9 Children of group B *P-value 10 Children of group A  9 Children of group B *P-value
Body-weight (kg) 16.0 12.5-29.3) 26 (21.3-60.5) NA 16.1 (13.5-28.6) 25.8 (22.2-61.3) NA
Dose mg/kg 4.1 (3.6-4.4) 4.0 (2.5-4.9) 0.54 8.3 (7.4-8.5) 7.8 (4.9-9.3) 0.65
AUC0-24 h (µg*h/ml) 7.60 (6.12-9.45) 10.5 (882-12.63) 0.05 8.80 (7.43-10.34) 11.04 (9.06-13.4) 0.12
Peak conc. (µg/ml) 0.94 (0.78-1.13) 1.34 (1.08-1.67) 0.03 1.72 (1.48-1.99) 2.59 (2.04-3.28) 0.01
Cmin (µg/ml) 0.068 (<0.05-0.15) 0.037 (<0.050-0.11) NA 0.050 (<0.050-0.076) 0.061 (<0.050-0.074) NA
TBC/F (L/h/kg) 1.09 (0.89-1.34) 0.73 (0.63-0.85) 0.13 0.92 (0.78-1.08) 0.69 (0.55-0.87) 0.07

TBC = total body clearance. F = oral bioavailability. NA = not available. Cmin = lamivudine minimum concentration. *Student t test for unpaired data

 

Table 5. Pharmacokinetic parameters of lamivudine which are obtained in the maternal plasma and in the beast-milk of 30 Ugandan and 29 Nigerian lactating women. Figures are the median and (interquartile range), by Waitt et al. [39]

  Estimated values in plasma     Estimated values in breast-milk      
Dose Tmax (h) Peak conc. (µg/ ml) AUC0-12 h (µg*h/ml) Tmax (h) Peak conc. (µg/ ml) AUC0-12 h (µg*h/ml) AUC0-12 h Milk/plasma ratio
150 mg twicedaily 4 (2 – 4) 0.64 (0.64 – 0.75) 3.34 (2.82 – 3.74) 6 (4 – 6) 0.91 (0.77 -1.10) 5.94 (5.26 – 6.13) 1.65 (1.59 – 1.92)
300 mg once-daily 2 (1.5 – 3) 0.91 (0.63 – 1,11) 4.54 (3.16 – 5.99) 6 (4 – 8) 0.63 (0.44 – 0.89) 4.42 (2.11 – 5.50) 0.95 (0.82 – 1.15)

is 12 hours, and lamivudine is primarily eliminated unchanged in the urine [1]. The oral dose of lamivudine is 4 mg/kg twicedaily in infants and it may be administered alone or combined with two or more antiviral drugs [2]. In children, the oral dose of lamivudine is computed according to the child age and the body-weight and the maximum dose is 300 mg once-daily [4]. Lamivudine has been found efficacy and safe in infants and children even when it is combined with other antiviral drugs [5-7]. The treatment with lamivudine plus nevirapine and zidovudine has been found efficacy and safe in infants with HIV-infection [5], and lamivudine co-administered with zidovudine is safe and effective in preventing maternal-to-infant HIV transmission [6]. Lamivudine plus zidovudine and lopinavir/ritonavir is efficacy and safe in children with HIV-infection [7]. Lamivudine prevents the transmission of hepatitis B virus from mother-to-infant [8- 16]. Lamivudine decreases the transmission of hepatitis B virus from the mothers to their newborn infants [8-13], lamivudine therapy is efficacious and safe in infants with chronic hepatitis B infection [14], the treatment with lamivudine and telbivudine [15] or lamivudine plus tenofovir [16] prevents the transmission of hepatitis B virus from infected mothers to their newborn infants. The median elimination half-life of lamivudine is about 6 in infants and 4 hours in infants and children [17-18]. The total body clearance is lower in infants than in infants and children, the distribution volume is about 3 L/kg in these infants and children and it is not affected by infant maturation and child development [18]. The co-administration of zidovudine with lamivudine causes modest effects on the pharmacokinetic parameters of lamivudine [19]. Lamivudine administered at a dose of 4 mg/kg twice-daily or at a dose of 8 mg/kg once-daily produces similar pharmacokinetic parameters with the exception of the total body clearance which is higher following a dose of 8 mg/kg once-daily [20]. Lamivudine interacts with drugs [21-23]. Dolutegravir co-administered with lamivudine increase the risk of toxicity [21], the renal clearance of lamivudine is decreased when lamivudine is co-administered with drugs that inhibit the renal transport [22], and trimethoprim-sulfamethoxazole increases the plasma concentration of lamivudine [23]. The prophylaxis with lamivudine has been described in infants and children [24-27]. The prophylaxis of infants infected by HIV-1 with lopinavir/ritonavir is not superior to that with lamivudine and prevents the HIV-1-infection in infants [24-25]. The prophylaxis with zidovudine plus lamivudine or with didanosine [26] and that with zidovudine plus lopinavir/ritonavir and lamivudine [27] prevents HIV-1-infection in children. The treatment with zidovudine has been studied in infants and children [28-35]. The treatment with lamivudine plus zidovudine and lopinavir/ ritonavir successfully treated infants with HIV-infection [28],treatment with lopinavir/ritonavir is superior to that with lamivudine [29], and lamivudine treatment reduces the risk of hepatitis B virus in newborn infants [30]. Children exposed to lopinavir/ritonavir or to lamivudine produce comparable growth and neuropsychological outcomes without evidence of adverseeffects [31]. Lamivudine monotherapy should be administered temporarily and should be considered a default option in children with virological failure [32] and lamivudine administered for one year is effective and well tolerated in children with Hepatitis B virus infection [33]. Lamivudine plus zidovudine is an effective treatment in children with HIV disease [34]. The treatment with lamivudine in children exhibits virological activity but the combination of lamivudine with antiretrovirals dugs is preferred [35]. Lamivudine freely crosses the human placenta [23-38] and freely migrates into the breast-milk [39-41].

In conclusion, lamivudine is a cytidine analogue reverse transcriptase that is active against HIV-1, HIV-2 and HBV. Lamivudine is approved for HIV in adults and children aged 3 months or older, but lamivudine is often co-administered with other antiviral drugs. Lamivudine is converted into lamivudine 5’-triphosphate which is the active anabolite. Lamivudine is administered orally, the oral bioavailability is 86%, and lamivudine is primarily eliminated in the urine. The oral dose of lamivudine is 4 mg/kg twice-daily in infants, and in children it is computed according to the child age and body-weight and the maximum dose is 300 mg once-daily. Lamivudine coadministered with other antiviral drugs has been found efficacy and safe in infants and children with HIV-infection and prevents the transmission of hepatitis B virus from infected mothers to their newborn infants. The elimination half-life of lamivudine is about 6 hours in infants and it is about 4 hours in infants and children. The prophylaxis and the treatment with lamivudine have been extensively investigated in infants and children. Lamivudine freely crosses the human placenta and freely migrates into the breast-milk. The aim of this study is to review the clinical pharmacology of lamivudine in infants and children.

 

REFERENCES

1. Flexner CV. Antiretroviral Agents and Treatment of HIV Infection. In The Goodman & Gilman’s. Pharmacol. Ther. 2018; 1037-1157.

2. Neonatal Formulary. “Lamivudine”. Oxford University Press. 8th Edition, Great Clarendon Street, Oxford, OX2, 6DP, UK, 2020: 431-433.

3. Young TE, Mangum B. NEOFAX®. “Lamivudine”. Thomas Reuters Clinical Editorial Staff, 23rd Edition, Montvale, USA, 2010; pp: 56-57.

4. The British national formulary for children. “Lamivudine”. Macmillan, 78th Edition, Hampshire International Business Park, Hampshire,Lime Three Way, Basingstoke, Hampshire, UK, 2019-2020; pp: 431- 433.

5. Maswabi K, Ajibola G, Bennett K, Capparelli EV, ean-Philippe P, et al. Safety and Efficacy of Starting Antiretroviral Therapy in the First Week of Life. Clin Infect Dis. 2021; 72: 388-393.

6. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, Berrebi A, Bénifla JL,et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA. 2001; 285: 2083-2093.

7. Owor M, Tierney C, Ziemba L, Browning R, Moye J, et al. Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092. Pediatr Infect Dis J. 2021; 40: 446-452.

8. Su G-G, Pan K-H, Zhao N-F, Fang S-H, Yang D-H, et al. Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy. World J Gastroenterol. 2004; 10: 910-912.

9. Pan X, Chen J, Zhou L, Ou X, He F, Liu Y, et al. Efficacy and safety of continuous antiviral therapy from preconception to prevent perinatal transmission of hepatitis B virus. Sci Rep. 2020;

10: 13631. 10.Khalighinejad P, Alavian SM, Fesharaki MG, Jalilianhasanpour R. Lamivudine’s efficacy and safety in preventing mother-to-child transmission of hepatitis B: A meta-analysis. Turk J Gastroenterol. 2019; 30: 66-74.

11.Han L, Zhang H-W, Xie J-X, Zhang Q, Wang H-Y, et al. A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus. World J Gastroenterol. 2011; 17: 4321-4333

. 12.Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010; 116: 147-159.

13.Luo A, Jiang X, Hong H. Lamivudine therapy for chronic hepatitis B in children: a meta-analysis. Virol J. 2019; 16: 88.

14.Li Z, Duan X, Hu Y, Zhou M, Liu M, et al. Efficacy and Safety of Lamivudine or Telbivudine in Preventing Mother-to-Child Transmission of Hepatitis B Virus: A Real-World Study. Biomed Res Int. 2020; 2020:1374276.

15.Bang NV, Anh LTL, Nguyen Van Anh T, Th N Mai Q, Tuong Van VT, et al. Efficacy and Safety of Tenofovir and Lamivudine in Late Pregnancy for Preventing Perinatal Transmission of Hepatitis B Virus in Highly Viremic Mothers. Ann Clin Lab Res. 2015; 3: 29-35.

16.Mirochnick M, Karin Nielsen-Saines K, Pilotto JH. Pilotto J, Veloso VG. Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. 2011; 30: 769-772.

17.Tremoulet AH, Capparelli EV, Patel P, Acosta EP, Luzuriaga K, et al. Population Pharmacokinetics of Lamivudine in Human Immunodeficiency Virus-Exposed and -Infected Infants. Antimicrob Agents Chemother. 2007; 51: 4297-4302.

18.Moodley J, Moodley D, Pillay K, Coovadia H, Saba J, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when co-administered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J Infect Dis. 1998; 178: 1327-1333.

19.Bergshoeff A, Burger D, Verweij C, Farrelly L, Flynn J, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther. 2005; 10: 239-246.

20.Cattaneo D, Capetti A, Rizzardini G. Drug-drug interactions of a twodrug regimen of dolutegravir and lamivudine for HIV treatment. Expert Opin Drug Metab Toxicol. 2019; 15: 245-252. 

21.Müller F, König J, Hoier E, Mandery K, Fromm MF. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol. 2013; 86: 808-815.

22.Taburet AM, Singlas E. Drug interactions with antiviral drugs. Clin Pharmacokinet. 1996; 30: 385-401.

23.Nagot N, Kankasa C, Tumwine JK, Meda N, Hofmeyr GJ, et al. Extended pre-exposure prophylaxis with lopinavir-ritonavir versus lamivudine to prevent HIV-1 transmission through breastfeeding up to 50 weeks in infants in Africa (ANRS 12174): a randomised controlled trial. Lancet. 2016; 387: 566-573.

24.Nagot N, Kankasa C, Meda N, Hofmeyr J, Nikodem C, et al. Lopinavir/ Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174. BMC Infect Dis. 2012; 12: 246.

25.McKinney RE, Johnson GM, Stanley K, Yong FH, Keller A, et al. A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team. J Pediatr. 1998; 133: 500-508.

26.Penazzato M, Dominguez K, Cotton M, Barlow-Mosha L, Ford N. Choice of antiretroviral drugs for postexposure prophylaxis for children: a systematic review. Clin Infect Dis. 2015; 60: 177-181.

27.Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, et al. Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure. N Engl J Med 2010; 363: 1510-1520.

28.Blanche S, Tylleskär T, Peries M, Kankasa C, Engebretsen I, et al. Growth in HIV-1-exposed but uninfected infants treated with lopinavir-ritonavir versus lamivudine: a secondary analysis of the ANRS 12174 trial. Lancet HIV. 2019; 6: 307-314.

29.van Zonneveld M, van Nunen AB, Niesters HGM, de Man RA, Schalm SW, et al. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2003; 10: 294-297.

30.Nagot N, Singata-Madliki M, Cournil A, Nalugya J, Tassembedo S, et al. Growth, clinical and neurodevelopmental outcomes at school age are similar for children who received 1-year lamivudine or lopinavir/ ritonavir HIV prophylaxis in early life. Sci Rep. 2021; 11: 3173.

31.Fairlie L, Bernheimer J, Sipambo N, Fick C, Kuhn L. Lamivudine monotherapy in children and adolescents: The devil is in the detail. S Afr Med J. 2017; 107: 1055-1057.

32.Liberek A, Szaflarska-Pop?awska A, Korzon M, ?uczak G, Góra-Gebka M, et al. Lamivudine therapy for children with chronic hepatitis B. World J Gastroenterol. 2006; 12: 2412-2416.

33.Perry CM, Faulds D. Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. Drugs. 1997; 53: 657-680.

34.Lewis LL, Venzon D, Church J, Farley M, Wheeler S, et al. Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group. J Infect Dis. 1996; 174: 16- 25.

35.Benaboud S, Tréluyer J-M, Urien S, Blanche S, Bouazza N, et al. Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women. Antimicrob Agents Chemother. 2012; 56: 776-782

36..Chappuy H, Tréluyer J-M, Jullien V, Dimet J, Rey E, et al. Maternalfetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus- infected pregnant women. Antimicrob Agents Chemother. 2004; 48: 4332-4336.

37.Mandelbrot L, Peytavin G, Firtion G, Farinotti R. Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol. 2001; 184: 153-158.

38.Waitt C, Olagunju A, Nakalema S, Kyohaire I, Owen A, et al. Plasma and breast milk pharmacokinetics of emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing African mother-infant pairs. J Antimicrob Chemother. 2018; 73: 1013-1019.

39.Giuliano M,Guidotti G, Andreotti M, Pirillo MF, Villani P, et al. Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load: a study within the Drug Resource Enhancement Against AIDS and Malnutrition Program. J Acquir Immune Defic Syndr. 2007; 44: 286-291.

40.Shapiro RL, Holland DT, Capparelli E, Lockman S, Thior I, et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis. 2005; 192: 720-727.

 

Pacifici GM (2021) Clinical pharmacology of lamivudine administered alone, or co-administered with other antiviral drugs, in infants and children. J Drug Des Res 8(2): 1086.

Received : 24 Jul 2021
Accepted : 11 Aug 2021
Published : 13 Aug 2021
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X