To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound [tenofovir] by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells. After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid.
◉ Summary of Use during Lactation:Tenofovir is available in the U.S. in two forms, tenofovir disoproxil fumarate and tenofovir alafenamide. Both release tenofovir, but tenofovir disoproxil fumarate releases tenofovir in the bloodstream whereas tenofovir alafenamide enters cells before releasing tenofovir. Most published experience is with tenofovir disoproxil fumarate in HIV therapy and prophylaxis. Exposure of the breastfed infant to tenofovir is trivial in HIV-positive mothers and HIV-negative mothers treated for HIV prophylaxis or hepatitis B infection. Some data indicate that tenofovir milk levels decrease with time after delivery. Among HIV-positive mothers who have breastfed during tenofovir disoproxil fumarate therapy no infant adverse effects have occurred up to 2 years of age. Tenofovir alfenamide use results in even lower milk levels and infant dosages than tenofovir disoproxil fumarate. In the US and other countries where access to clean water and affordable replacement feeding are available, it is recommended that mothers living with HIV not breastfeed their infants to avoid postnatal transmission of HIV-1 infection. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision.
Pre-exposure prophylaxis (PrEP) regimens containing tenofovir are acceptable for use in HIV-negative nursing mothers. Maternal use of prophylactic vaginal tenofovir (investigational in the U.S.) also does not appear to present a risk to the breastfed infant. In hepatitis B, expert reviews of available data and most professional guidelines state that there is no justification for contraindicating the use of tenofovir during breastfeeding. One guideline suggests discussing the lack of long-term safety data with the mother. No differences exist in infection rates between breastfed and formula-fed infants born to hepatitis B-infected women, as long as the infant receives hepatitis B immune globulin and hepatitis B vaccine at birth.
◉ Effects in Breastfed Infants:Two newborn infants whose mothers were treated with tenofovir 245 mg (presumably 300 mg of tenofovir disoproxil fumarate) daily were exclusively breastfed for 3 months. At 4 months of age, neither showed any adverse outcomes on standard developmental parameters.
Five women with hepatitis B infection were treated with tenofovir disoproxil fumarate 300 mg daily beginning in the third trimester of pregnancy and continuing postpartum. Although instructed not to breastfeed, 5 mothers breastfed (extent not stated) their newborn infants. No short-term adverse reactions were seen and the infants’ HBsAg was negative between 28 and 36 weeks of age.
Fourteen mothers were treated with tenofovir disoproxil fumarate (dosage unspecified) during pregnancy (12 beginning in the first trimester) for hepatitis B. Three of the mothers breastfed while taking tenofovir. No adverse outcomes were noted in their breastfed infants up to 1 year of age.
In a study of 50 infants breastfed by HIV-negative women who were given pre-exposure prophylaxis daily with the combination of tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg by directly observed therapy for 10 days, 2 infants reportedly had diarrhea lasting 2 to 3 days. No other side effects were reported.
A study of 136 breastfed infants of mothers who took tenofovir disoproxil fumarate, efavirenz and lamivudine during pregnancy and postpartum (Option B+) in Malawi measured bone markers at 1, 6 and 12 months of age. Markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants’ bone markers in the study.
In a long-term study of tenofovir disoproxil fumarate for chronic hepatitis B, 3 women reportedly breastfed their infants (extent not stated). None of the infants had any adverse effects up to 1 year of age.
A study of pregnant women with hepatitis B infection in China enrolled 143 women. Tenofovir disoproxil fumarate 300 mg daily was given starting at 22 to 33 weeks of pregnancy and continued postpartum. Thirty-one mothers breastfed (extent not stated) their infants who received standard hepatitis B prophylaxis. At 28 weeks postpartum, infant physical and neurologic development was within national standards and none had developed hepatitis B infection. Mild side effects of cough and fever were reported in >5% of infants. Less frequent reactions included skin rash, diarrhea, vomiting, jaundice and pneumonia. All adverse effects were judged not to be related to the drug by the authors.
In a study of 17 nursing mothers who receive 40 mg of 1% vaginal tenofovir gel daily for 6 days, 4 of 17 infants had one or more adverse effects. There were a total of 8 adverse reactions. Seven were mild, and one had diarrhea that was thought to be related to tenofovir exposure.
A prospective cohort study in Malawi compared the infants of HIV+ mothers taking tenofovir disoproxil fumarate and efavirenz (n = 260) to infants of mothers who were HIV negative (n = 125). Infants were followed for growth and development for up to 18 months at which time there were 169 mother-infant pairs in the treatment group and 54 in the HIV-negative group. No difference was found in the growth and development of the breastfed infants of treated women compared to the infants of untreated mothers.
Thirty women with hepatitis B were treated with tenofovir disoproxil fumarate 300 mg daily from week 24 to 32 of pregnancy and until three months postpartum. Their breastfed infants (extent not stated) had no abnormal signs or symptoms reported during maternal therapy. The physical growth parameters (height, weight and head circumference) stratified by sex of infants at birth, 3, 6 and 12 months postpartum were normal.
◉ Effects on Lactation and Breastmilk:A preliminary study of Ugandan women compared the milk composition of women receiving a tenofovir-based regimen for HIV to that of women who were not infected with HIV. Women with HIV on tenofovir-based antiretroviral therapy had higher milk calcium in the first months of lactation (193 and 188 mg/L compared to 177 and 172 mg/L at 2 and 14 weeks postpartum, respectively) and a greater overall reduction in the first year of lactation than women without HIV (10 and 23% decrease compared to 8% and 16% decrease at 6 and 12 months). However, the only statistically significant differences were at 14 weeks postpartum for serum calcium and at 6 to 12 months for the percentage decrease in serum calcium in the HIV-infected women.
Tenofovir alafenamide is reported to bind to plasma proteins and _ex vivo_ studies have registered that approximately 80% of the administered dose of this drug is presented in a bound state.
As compared to the parent molecule, [tenofovir], tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability. Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng\*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation. Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal exposure.
Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged [tenofovir] followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir.
The reported clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 L/h.
[EN] A RECYCLING PROCESS FOR PREPARING TENOFOVIR ALAFENAMIDE DIASTEREOMERS [FR] PROCESSUS DE RECYCLAGE PERMETTANT DE PRÉPARER DES DIASTÉRÉOISOMÈRES DE TÉNOFOVIR ALAFÉNAMIDE
Polymer-of-prodrug (POP) materials enable new nucleoside reverse transcriptase inhibitor (NRTI) therapy strategies. The materials are prodrugs of NRTIs in the form of polymers. Suitable materials include products which are polymeric NRTI delivery systems comprising polymeric materials which are capable of degradation after administration to release NRTIs or NRTI prodrugs which themselves are capable of metabolism to the parent NRTIs. The NRTIs may optionally be selected from tenofovir (TFV), emtricitabine (FTC), lamivudine (3TC) and MK-8591 (EFdA). The invention facilitates long-acting (LA) regimens. Constructs of the materials may be in the form of injectable compositions or implants.
PHOSPHORIC ACID/PHOSPHONIC ACID DERIVATIVES AND MEDICINAL USES THEREOF
申请人：BEIJING MEIBEITA DRUG RES CO., LTD.
公开号：US20160115186A1
公开（公告）日：2016-04-28
The present invention relates to phosphoric acid/phosphonic acid derivatives shown by formula (I), wherein, R
1
or R
2
represents the following structures: (Q1), or (Q2), or (Q3). Q1 represents ester derivatives of L-amino acid, wherein R
3
is alkyl with 1-6 carbon atoms or cycloalkyl, R
4
is H or alkyl with 1-6 carbon atoms; Q2 represents hydroxyl substituted benzodioxane derivatives; Q3 represents hydroxyl substituted benzodioxolane derivatives; R
1
or R
2
is the same or different, but at least one of them is Q2 or Q3; D represents residues of pharmacologically active molecules containing a phosphate/phosphonate group, i.e. formula (II) represents pharmacologically active molecules containing a phosphate/phosphonate group; and when R
1
and R
2
are different, the configuration of the P atom connected to R
1
and R
2
is of R or S type.
Disclosed herein, inter alia, are acyclic nucleotide analogs and methods of using an acyclic nucleotide analog for treating and/or ameliorating a papillomavirus infection.
